Novel heterocyclic analogs of diphenylethylene compounds

ABSTRACT

Novel diphenylethylene compounds and derivatives thereof containing thiazolidinedione or oxazolidinedione moieties are provided which are effective in lowering blood glucose level, serum insulin, triglyceride and free fatty acid levels in animal models of Type II diabetes. The compounds are disclosed as useful for a variety of treatments including the treatment of inflammation, inflammatory and immunological diseases, insulin resistance, hyperlipidemia, coronary artery disease, cancer and multiple sclerosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.10/265,902, filed Oct. 8, 2002, which is a continuation-in-part of U.S.patent application Ser. No. 09/843,167, filed Apr. 27, 2001, which is acontinuation-in-part of U.S. patent application Ser. No. 09/785,554,filed Feb. 20, 2001, which is a continuation-in-part of U.S. patentapplication Ser. No. 09/591,105, filed on Jun. 9, 2000, and whichfurther is a continuation-in-part of U.S. patent application Ser. No.09/287,237, filed on Apr. 6, 1999.

BACKGROUND OF THE INVENTION

The present application is directed to novel compounds formed bychemically coupling diphenylethylene compounds and derivatives thereofwith thiazolidine or oxazolidine intermediates. These compounds areeffective for providing a variety of useful pharmacological effects. Forexample, the compounds are useful in lowering blood glucose, seruminsulin and triglyceride levels in animal models of type II diabetes.

Furthermore, these compounds are useful for treatment of disordersassociated with insulin resistance, such as polycystic ovary syndrome,as well as hyperlipidemia, coronary artery disease and peripheralvascular disease, and for the treatment of inflammation andimmunological diseases, particularly those mediated by cytokines andcyclooxygenase such as TNF-alpha, IL-1, IL-6 and/or COX-2.

The causes of type I and type II diabetes are yet unknown, although bothgenetics and environment seem to be major factors. Insulin dependenttype I and non-insulin dependent type II are the types which are known.Type I is an autoimmune disease in which the responsible autoantigen isstill unknown. Patients of type I need to take insulin parenterally orsubcutaneously to survive. However, type II diabetes, the more commonform, is a metabolic disorder resulting from the body's inability tomake a sufficient amount of insulin or to properly use the insulin thatis produced. Insulin secretion and insulin resistance are considered themajor defects, however, the precise genetic factors involved in themechanism remain unknown.

Patients with diabetes usually have one or more of the followingdefects:

-   Less production of insulin by the pancreas;-   Over secretion of glucose by the liver;-   Decreased glucose uptake by the skeletal muscles;-   Defects in glucose transporters; and-   Desensitization of insulin receptors.

Other than the parenteral or subcutaneous application of insulin, thereare about 4 classes of oral hypoglycemic agents used. TABLE 1 ClassApproved Drugs Mode of Action Limitations Sulfonylurea 4 (1^(st)generation) Acts on pancreas development of and to release moreresistance 2 (2^(nd) generation) insulin Biguanides Metformin Reducesglucose liver problems, production by lactic acidosis liver; improvesinsulin sensitivity Alpha′- Acarbose Interferes with only useful atglucosidase digestive process; postprandial inhibitor reduces glucoselevel absorption Thiazolidinedione Troglitazone Reduce insulin ″add-on″with (withdrawn) resistancy insulin; not Rosiglitazone useful forPioglitazone people with heart and liver disease

As is apparent from the above table, each of the current agentsavailable for use in treatment of diabetes has certain disadvantages.Accordingly, there is a continuing interest in the identification anddevelopment of new agents, particularly, water soluble agents which canbe orally administered, for use in the treatment of diabetes.

The thiazolidinedione class listed in the above table has gained morewidespread use in recent years for treatment of type II diabetes,exhibiting particular usefulness as insulin sensitizers to combat“insulin resistance”, a condition in which the patient becomes lessresponsive to the effects of insulin. However, the knownthiazolidinediones are not effective for a significant portion of thepatient population. In addition, the first drug in this class to beapproved by the FDA, troglitazone, was withdrawn from the market due toproblems of liver toxicity. Thus, there is a continuing need fornontoxic, more widely effective insulin sensitizers.

Pharmaceutical compositions and methods utilizing thiazolidinediones aredescribed in U.S. Pat. Nos. 6,133,295; 6,133,293; 6,130,216; 6,121,295;6,121,294; 6,117,893; 6,114,526; 6,110,951; 6,110,948; 6,107,323;6,103,742; 6,080,765; 6,046,222; 6,046;202; 6,034,110; 6,030,973;RE36,575; 6,011,036; 6,011,031; 6,008,237; 5,990,139; 5,985,884;5,972,973 and others.

As indicated above, the present invention is also concerned withtreatment of immunological diseases or inflammation, notably suchdiseases as are mediated by cytokines or cyclooxygenase. The principalelements of the immune system are macrophages or antigen-presentingcells, T cells and B cells. The role of other immune cells such as NKcells, basophils, mast cells and dendritic cells are known, but theirrole in primary immunologic disorders is uncertain. Macrophages areimportant mediators of both inflammation and providing the necessary“help” for T cell stimulation and proliferation. Most importantlymacrophages make IL 1, IL 12 and TNF-alpha, all of which are potentpro-inflammatory molecules and also provide help for T cells. Inaddition, activation of macrophages results in the induction of enzymes,such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (NOS)and production of free radicals capable of damaging normal cells. Manyfactors activate macrophages, including bacterial products,superantigens and interferon gamma (IFNγ). It is believed thatphosphotyrosine kinases (PTKs) and other undefined cellular kinases areinvolved in the activation process.

Macrophages take up and break down antigens into small fragments. Thesefragments then associate with the major histocompatibility complex II(MHC II). This complex of antigen fragments and MHC II is recognized bythe T cell receptor. In association with appropriate co-stimulatorysignals this receptor-ligand interaction leads to the activation andproliferation of T cells. Depending on the route of administration ofantigen, their dose and the conditions under which macrophages areactivated, the immune response can result in either B cell help andantibody production or on the development of cell mediated response.Since macrophages are sentinel to the development of an immune response,agents that modify their function, specifically their cytokine secretionprofile, are likely to determine the direction and potency of the immuneresponse.

Cytokines are molecules secreted by immune cells that are important inmediating immune responses. Cytokine production may lead to thesecretion of other cytokines, altered cellular function, cell divisionor differentiation. Inflammation is the body's normal response to injuryor infection. However, in inflammatory diseases such as rheumatoidarthritis, pathologic inflammatory processes can lead to morbidity andmortality. The cytokine tumor necrosis factor-alpha (TNF-alpha) plays acentral role in the inflammatory response and has been targeted as apoint of intervention in inflammatory disease. TNF-alpha is apolypeptide hormone released by activated macrophages and other cells.At low concentrations, TNF-alpha participates in the protectiveinflammatory response by activating leukocytes and promoting theirmigration to extravascular sites of inflammation (Moser et al., J ClinInvest, 83:444-55, 1989). At higher concentrations, TNF-alpha can act asa potent pyrogen and induce the production of other pro-inflammatorycytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan etal., Lancet, 2:244-7, 1989). TNF-alpha also stimulates the synthesis ofacute-phase proteins. In rheumatoid arthritis, a chronic and progressiveinflammatory disease affecting about 1% of the adult U.S. population,TNF-alpha mediates the cytokine cascade that leads to joint damage anddestruction (Arend et al., Arthritis Rheum, 38:151-60, 1995). Inhibitorsof TNF-alpha, including soluble TNF receptors (etanercept) (Goldenberg,Clin Ther, 21:75-87, 1999) and anti-TNF-alpha antibody (infliximab)(Luong et al., Ann Pharmacotherapy, 34:743-60, 2000), have recently beenapproved by the U.S. Food and Drug Administration (FDA) as agents forthe treatment of rheumatoid arthritis.

Elevated levels of TNF-alpha have also been implicated in many otherdisorders and disease conditions, including cachexia (Fong et al., Am JPhysiol, 256:8659-65, 1989), septic shock syndrome (Tracey et al., ProcSoc Exp Biol Med, 200:233-9, 1992), osteoarthritis (Venn et al.,Arthritis Rheum, 36:819-26, 1993), inflammatory bowel disease such asCrohn's disease and ulcerative colitis (Murch et al., Gut, 32:913-7,1991), Behoet's disease (Akoglu et al., J Rheumatol, 17:1107-8, 1990),Kawasaki disease (Matsubara et al., Clin Immunol Immunopathol, 56:29-36,1990), cerebral malaria (Grau et al., N Engl J Med, 320:1586-91, 1989),adult respiratory distress syndrome (Millar et al., Lancet 2:712-4,1989), asbestosis and silicosis (Bissonnette et al., Inflammation,13:329-39, 1989), pulmonary sarcoidosis (Baughman et al., J Lab ClinMed, 115:36-42, 1990), asthma (Shah et al., Clin Exp Allergy,25:1038-44, 1995), AIDS (Dezube et al., J Acquir Immune Defic Syndr,5:1099-104, 1992), meningitis (Waage et al., Lancet, 1:355-7, 1987),psoriasis (Oh et al., J Am Acad Dermatol, 42:829-30, 2000), graft versushost reaction (Nestel et al., J Exp Med, 175:405-13, 1992), multiplesclerosis (Sharief et al., N Engl J Med, 325:467-72, 1991), systemiclupus erythematosus (Maury et al., Int J Tissue React, 11:189-93, 1989),diabetes (Hotamisligil et al., Science, 259:87-91, 1993) andatherosclerosis (Bruunsgaard et al., Clin Exp Immunol, 121:255-60,2000).

It can be seen from the references cited above that inhibitors ofTNF-alpha are potentially useful in the treatment of a wide variety ofdiseases. Compounds that inhibit TNF-alpha have been described in U.S.Pat. Nos. 6,090,817; 6,080,763; 6,080,580; 6,075,041; 6,057,369;6,048,841; 6,046,319; 6,046,221; 6,040,329; 6,034,100; 6,028,086;6,022,884; 6,015,558; 6,004,974; 5,990,119; 5,981,701; 5,977,122;5,972,936; 5,968,945; 5,962,478; 5,958,953; 5,958,409; 5,955,480;5,948,786; 5,935,978; 5,935,977; 5,929,117; 5,925,636; 5,900,430;5,900,417; 5,891,883; 5,869,677 and others.

Interleukin-6 (IL-6) is another pro-inflammatory cytokine that exhibitspleiotropy and redundancy of action. IL-6 participates in the immuneresponse, inflammation and hematopoiesis. It is a potent inducer of thehepatic acute phase response and is a powerful stimulator of thehypothalamic-pituitary-adrenal axis that is under negative control byglucocorticoids. IL-6 promotes the secretion of growth hormone butinhibits release of thyroid stimulating hormone. Elevated levels of IL-6are seen in several inflammatory diseases, and inhibition of the IL-6cytokine subfamily has been suggested as a strategy to improve therapyfor rheumatoid arthritis (Carroll et al., Inflamm Res, 47:1-7, 1998). Inaddition, IL-6 has been implicated in the progression of atherosclerosisand the pathogenesis of coronary heart disease (Yudkin et al.,Atherosclerosis, 148:209-14, 1999). Overproduction of IL-6 is also seenin steroid withdrawal syndrome, conditions related to deregulatedvasopressin secretion, and osteoporosis associated with increased boneresorption, such as in cases of hyperparathyroidism and sex-steroiddeficiency (Papanicolaou et al., Ann Intern Med, 128:127-37, 1998).

Since excessive production of IL-6 is implicated in several diseasestates, it is highly desirable to develop compounds that inhibit IL-6secretion. Compounds that inhibit IL-6 have been described in U.S. Pat.Nos. 6,004,813; 5,527,546 and 5,166,137.

Cyclooxygenase is an enzyme that catalyzes a rate-determining step inthe biosynthesis of prostaglandins, which are important mediators ofinflammation- and pain. The enzyme occurs as at least two distinctisomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). TheCOX-1 isomer is constitutively expressed in the gastric mucosa,platelets and other cells and is involved in the maintenance ofhomeostasis in mammals, including protecting the integrity of thedigestive tract. The COX-2 isomer, on the other hand, is notconstitutively expressed but rather is induced by various agents, suchas cytokines, mitogens, hormones and growth factors. In particular,COX-2 is induced during the inflammatory response (DeWitt D L, BiochimBiophys Acta, 1083:121-34, 1991; Seibert et al., Receptor, 4:17-23,1994.). Aspirin and other conventional non-steroid anti-inflammatorydrugs (NSAIDs) are non-selective inhibitors of both COX-1 and COX-2.They can be effective in reducing inflammatory pain and swelling, butsince they hamper the protective action of COX-1, they produceundesirable side effects of gastrointestinal pathology. Therefore,agents that selectively inhibit COX-2 but not COX-1 are preferable fortreatment of inflammatory diseases. Recently, a diarylpyrazolesulfonamide (celecoxib) that selectively inhibits COX-2 has beenapproved by the FDA for use in the treatment of rheumatoid arthritis(Luong et al., Ann Pharmacother, 34:743-60, 2000; Penning et al., J MedChem, 40:1347-65, 1997). COX-2 is also expressed in many cancers andprecancerous lesions, and there is mounting evidence that selectiveCOX-2 inhibitors may be useful for treating and preventing colorectal,breast and other cancers (Taketo M M, J Natl Cancer Inst, 90:1609-20,1998; Fournier et al., J Cell Biochem Suppl, 34:97-102, 2000; Masferreret al., Cancer Res, 60:1306-11, 2000). In 1999 celecoxib was approved bythe FDA as an adjunct to usual care for patients with familialadenomatous polyposis, a condition which, left untreated, generallyleads to colorectal cancer.

Compounds that selectively inhibit COX-2 have been described in U.S.Pat. Nos. 5,344,991; 5,380,738; 5,434,178; 5,466,823; 5,474,995;5,510,368; 5,521,207; 5,521,213; 5,536,752; 5,550,142; 5,552,422;5,604,260; 5,639,780; 5,643,933; 5,677,318; 5,691,374; 5,698,584;5,710,140; 5,733,909; 5,789,413; 5,811,425; 5,817,700; 5,849,943;5,859,257; 5,861,419; 5,905,089; 5,922,742; 5,925,631; 5,932,598;5,945,539; 5,968,958; 5,981,576; 5,994,379; 5,994,381; 6,001,843;6,002,014; 6,004,950; 6,004,960; 6,005,000; 6,020,343; 6,034,256;6,046,191; 6,046,217; 6,057,319; 6,071,936; 6,071,954; 6,077,850;6,077,868; 6,077,869 and 6,083,969.

The cytokine IL-1 beta also participates in the inflammatory response.It stimulates thymocyte proliferation, fibroblast growth factoractivity, and the release of prostaglandin from synovial cells.

Elevated or unregulated levels of the cytokine IL-1 beta have beenassociated with a number of inflammatory diseases and other diseasestates, including but not limited to adult respiratory distress syndrome(Meduri et al, Chest 107:1062-73, 1995), allergy (Hastie et al, Cytokine8:730-8, 1996), Alzheimer's disease (O'Barr et al, J Neuroimmunol109:87-94, 2000), anorexia (Laye et al, Am J Physiol Regul Integr CompPhysiol 279:893-8, 2000), asthma (Sousa et al, Thorax 52:407-10, 1997),atherosclerosis (Dewberry et al, Arterioscler Thromb Vasc Biol20:2394-400, 2000), brain tumors (Ilyin et al, Mol Chem Neuropathol33:125-37, 1998), cachexia (Nakatani et al, Res Commun Mol PatholPharmacol 102:241-9, 1998), carcinoma (Ikemoto et al, Anticancer Res20:317-21, 2000), chronic arthritis (van den Berg et al, Clin ExpRheumatol 17:S105-14, 1999), chronic fatigue syndrome (Cannon et al, JClin Immunol 17:253-61, 1997), CNS trauma (Herx et al, J Immunol165:2232-9, 2000), epilepsy (De Simoni et al, Eur J Neurosci 12:2623-33,2000), fibrotic lung diseases (Pan et al, Pathol Int 46:91-9, 1996),fulminant hepatic failure (Sekiyama et al, Clin Exp Immunol 98:71-7,1994), gingivitis (Biesbrock et al, Monogr Oral Sci 17:20-31, 2000),glomerulonephritis (Kluth et al, J Nephrol 12:66-75, 1999),Guillain-Barre syndrome (Zhu et al, Clin Immunol Immunopathol 84:85-94,1997), heat hyperalgesia (Opree et al, J Neurosci 20:6289-93, 2000),hemorrhage and endotoxemia (Parsey et al, J Immunol 160:1007-13, 1998),inflammatory bowel disease (Olson et al, J Pediatr Gastroenterol Nutr16:241-6, 1993), leukemia (Estrov et al, Leuk Lymphoma 24:379-91, 1997),leukemic arthritis (Rudwaleit et al, Arthritis Rheum 41:1695-700, 1998),systemic lupus erythematosus (Mao et al, Autoimmunity 24:71-9, 1996),multiple sclerosis (Martin et al, J Neuroimmunol 61:241-5, 1995),osteoarthritis (Hernvann et al, Osteoarthritis Cartilage 4:13942, 1996),osteoporosis (Zheng et al, Maturitas 26:63-71, 1997), Parkinson'sdisease (Bessler et al, Biomed Pharmacother 53:141-5, 1999), POEMSsyndrome (Gherardi et al, Blood 83:2587-93, 1994), pre-term labor(Dudley, J Reprod Immunol 36:93-109, 1997), psoriasis (Bonifati et al, JBiol Regul Homeost Agents 11:133-6, 1997), reperfusion injury (Clark etal, J Surg Res 58:675-81, 1995), rheumatoid arthritis (Seitz et al, JRheumatol 23:1512-6, 1996), septic shock (van Deuren et al, Blood90:1101-8, 1997), systemic vasculitis (Brooks et al, Clin Exp Immunol106:273-9, 1996), temporal mandibular joint disease (Nordahl et al, EurJ Oral Sci 106:559-63, 1998), tuberculosis (Tsao et al, Tuber Lung Dis79:279-85, 1999), viral rhinitis (Roseler et al, Eur ArchOtorhinolaryngol Suppl 1:S61-3, 1995), and pain and/or inflammationresulting from strain, sprain, trauma, surgery, infection or otherdisease processes.

Since overproduction of IL-1 beta is associated with numerous diseaseconditions, it is desirable to develop compounds that inhibit theproduction or activity of IL-1 beta. Methods and compositions forinhibiting IL-1 beta are described in U.S. Pat. Nos. 6,096,728;6,090,775; 6,083,521; 6,036,978; 6,034,107; 6,034,100; 6,027,712;6,024,940; 5,955,480; 5,922,573; 5,919,444; 5,905,089; 5,874,592;5,874,561; 5,874,424; 5,840,277; 5,837,719; 5,817,670; 5,817,306;5,792,778; 5,780,513; 5,776,979; 5,776,954; 5,767,064; 5,747,444;5,739,282; 5,731,343; 5,726,148; 5,684,017; 5,683,992; 5,668,143;5,624,931; 5,618,804; 5,527,940; 5,521,185; 5,492,888; 5,488,032 andothers.

It will be appreciated from the foregoing that, while there have beenextensive prior efforts to provide compounds for inhibiting, forexample, TNF-alpha, IL-1, IL-6, COX-2 or other agents consideredresponsible for immune response, inflammation or inflammatory diseases,e.g. arthritis, there still remains a need for new and improvedcompounds for effectively treating or inhibiting such diseases. Aprincipal object of the invention is to provide compounds which areeffective for such treatments as well as for the treatment of, forexample, insulin resistance, hyperlipidemia, coronary heart disease,multiple sclerosis and cancer.

SUMMARY OF THE INVENTION

In one aspect of the invention, compounds of the following formula 1 areprovided:

wherein Z is

wherein n, m, q and r are independently integers from zero to 4 providedthat n+m≦4, and q+r≦4; p and s are independently integers from zero to 5provided that p+s≦5; a, b and c are double bonds which may be present orabsent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters can have theR— or S-configuration;

R and R′ are independently H, C₁-C₂₀ linear or branched alkyl, C₂-C₂₀linear or branched alkenyl, —CO₂Z′, wherein Z′ is H, sodium, potassium,or other pharmaceutically acceptable counter-ion such as calcium,magnesium, ammonium, tromethamine, tetramethylammonium, and the like;—CO₂R′″, —NH₂, —NHR′″, —NR₂′″, —OH, —OR′″, halo, substituted C₁-C₂₀linear or branched alkyl or substituted C₂-C₂₀ linear or branchedalkenyl, wherein R′″ is independently C₁-C₂₀ linear or branched alkyl,linear or branched alkenyl or aralkyl —(CH₂)_(x)—Ar, where x is 1-6;CONR₂″″, where R″″ is independently H, optionally substituted C₁-C₂₀alkyl, optionally substituted C₁-C₂₀ alkoxy, preferably an optionallysubstituted C₁-C₆ alkoxy (for example methoxy, ethoxy or propoxy),optionally substituted C₂-C₂₀ alkenyl or optionally substituted C₆-C₁₀aryl or where NR₂″″ represents a cyclic moiety such as morpholine,piperidine, piperazine and the like;

R″ is independently H, C₁-C₂₀ linear or branched alkyl, C₂-C₂₀ linear orbranched alkenyl, —CO₂Z′, wherein Z′ is H, sodium, potassium, or otherpharmaceutically acceptable counter-ion such as calcium, magnesium,ammonium, tromethamine, tetramethylammonium, and the like; —CO₂R′″,—NH₂, —NHR′″, —NR₂′″, —OH, —OR′″, halo, substituted C₁-C₂₀ linear orbranched alkyl or substituted C₂-C₂₀ linear or branched alkenyl whereinR′″ is independently C₁-C₂₀ linear or branched alkyl, linear or branchedalkenyl or aralkyl —(CH₂)_(x)—Ar, where x is 1-6;

A, A′ and A″ are independently H, C₁-C₂₀ acylamino;

C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;

C₁-C₂₀ alkoxycarbonyl; C₁-C₂₀ alkoxy;

C₁-C₂₀ alkylamino; C₁-C₂₀ alkylcarboxylamino; carboxyl; cyano; halo;hydroxy;

B, B′ and B″ are independently H;

C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;

C₁-C₂₀ alkenoyl; C₁-C₂₀ alkoxycarbonyl;

C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino;

C₁-C₂₀ alkylcarboxylamino; aroyl, aralkanoyl; carboxyl; cyano; halo;hydroxy; nitro;

optionally substituted, linear or branched C₁-C₂₀ alkyl or C₂-C₂₀alkenyl; or A and B together, or A′ and B′ together, or A″ and B″together, may be joined to form a methylenedioxy or ethylenedioxy group;

X, X′ are independently —NH, —NR′″, O or S.

In a further aspect of the invention, the following preferred compoundsof formula 1 are provided:

A)

-   -   wherein Z is    -   n, m, q and r independently represent integers from zero to 4        provided that n+m≦4 and q+r≦4; p and s independently represent        integers from zero to 5 provided that p+s≦5; a, b and c        represent double bonds which may be present or absent; when        present, the double bonds may be in the E or Z configuration        and, when absent, the resulting stereocenters may have the R— or        S-configuration;    -   R and R′ each independently represent a hydrogen atom; linear or        branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;        —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;        halogen atom; optionally substituted linear or branched C₁-C₂₀        alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl;    -   R″ independently represents a hydrogen atom; linear or branched        C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′;        —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; halogen atom;        optionally substituted linear or branched C₁-C₂₀ alkyl;        optionally substituted linear or branched C₂-C₂₀ alkenyl;    -   R′″ independently represents a linear or branched C₁-C₂₀ alkyl;        linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x        represents an integer from 1 to 6 and Ar represents aryl;    -   R″″ independently represents a hydrogen atom; optionally        substituted C₁-C₂₀ alkyl; optionally substituted C₁-C₂₀ alkoxy;        optionally substituted C₂-C₂₀ alkenyl; optionally substituted        C₆-C₁₀ aryl; or NR₂″″ represents a cyclic moiety;    -   Z′ represents a hydrogen atom or a pharmaceutically acceptable        counter-ion;    -   A, A′ and A″ each independently represent a hydrogen atom;        C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀        alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀        alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    -   B, B′ and B″ each independently represent; C₂-C₂₀ alkenoyl;        aroyl; aralkanoyl; nitro; optionally substituted, linear or        branched C₁-C₂₀ alkyl; or optionally substituted, linear or        branched C₂-C₂₀ alkenyl;    -   or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly,        independently represent a methylenedioxy or ethylenedioxy group;        and    -   X and X′ independently represent >NH, >NR′″, —O—, or —S—.

B)

-   -   wherein Z is    -   n, m, q and r independently represent integers from zero to 4        provided that n+m≦4 and q+r≦4; p and s independently represent        integers from zero to 5 provided that p+s≦5; a, b and c        represent double bonds which may be present or absent; when        present, the double bonds may be in the E or Z configuration        and, when absent, the resulting stereocenters may have the R— or        S-configuration;    -   R independently represents a hydrogen atom; linear or branched        C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′;        —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogen        atom; optionally substituted linear or branched C₁-C₂₀ alkyl;        optionally substituted linear or branched C₂-C₂₀ alkenyl;    -   R′ independently represents a hydrogen atom; linear or branched        C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′;        —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″; —CONR₂″″; halogen atom;        optionally substituted linear or branched C₁-C₂₀ alkyl;        optionally substituted linear or branched C₂-C₂₀ alkenyl;    -   R″ independently represents a hydrogen atom; linear or branched        C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′;        —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; halogen atom;        optionally substituted linear or branched C₁-C₂₀ alkyl;        optionally substituted linear or branched C₂-C₂₀ alkenyl;    -   R′″ independently represents a linear or branched C₁-C₂₀ alkyl;        linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x        represents an integer from 1 to 6 and Ar represents aryl;    -   R″″ independently represents a hydrogen atom; optionally        substituted C₁-C₂₀ alkyl; optionally substituted C₁-C₂₀ alkoxy;        optionally substituted C₂-C₂₀ alkenyl; optionally substituted        C₆-C₁₀ aryl; or NR₂″″ represents a cyclic moiety;    -   Z′ represents a hydrogen atom or a pharmaceutically acceptable        counter-ion;    -   A, A′ and A″ each independently represent a hydrogen atom;        C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀        alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀        alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    -   B, B′ and B″ each independently represent; C₂-C₂₀ alkenoyl;        aroyl; aralkanoyl; nitro; optionally substituted, linear or        branched C₁-C₂₀ alkyl; or optionally substituted, linear or        branched C₂-C₂₀ alkenyl;    -   or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly,        independently represent a methylenedioxy or ethylenedioxy group;        and    -   X and X′ independently represent >NH, >NR′″, —O—, or —S—.

These compounds are useful for treating diabetes, hyperlipidemia andother diseases linked to insulin resistance, such as coronary arterydisease and peripheral vascular disease, and also for treating orinhibiting inflammation or inflammatory diseases such as inflammatoryarthritides and collagen vascular diseases, which are caused by, forexample, cytokines or cyclooxygenase such as TNF-alpha, IL-1, IL-6and/or COX-2. The compounds are also useful for treating or preventingother diseases mediated by cytokines and/or cyclooxygenase, such ascancer.

Accordingly, the invention also provides a method of treating diabetesand related diseases comprising the step of administering to a subjectsuffering from a diabetic or related condition a therapeuticallyeffective amount of a compound of formula 1. Additionally, the inventionprovides a method of treating inflammation or inflammatory diseases ordiseases mediated by cytokines and/or cyclooxygenase by administering toa subject in need of such treatment an effective amount of a compoundaccording to Formula 1. Other uses will also be evident from thisspecification.

Pharmaceutical compositions containing a therapeutically effectiveamount of one or more compounds according to formula 1 together with apharmaceutically or physiologically acceptable carrier, for use in thetreatments contemplated herein, are also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show graphs of the blood glucose levels and bodyweights, respectively, of db/db (spontaneous diabetic) male mice given acompound according to the invention of a period of 15 days.

FIGS. 2A and 2B show graphs of the blood glucose levels and body weightsof ob/ob (genetically obese and spontaneously diabetic) male mice givena compound according to the invention over a period of 15 days.

FIGS. 3A and 3B with graphs of blood glucose levels of db/db mice andob/ob mice, respectively, given a compound according to the inventionover a period of 20-25 days.

FIG. 4 shows a graph of blood glucose level in db/db male mice over 72hours following a dosage of the compound.

FIGS. 5A, 5B, 5C and 5D show graphs of the triglyceride levels, freefatty acid levels, glyc-Hb levels and leptin levels in serum of thedb/db mice treated with a compound according to the present invention.

FIGS. 6A, 6B, 6C and 6D are graphs showing the serum insulin levels,triglyceride levels, free fatty acid levels and Glyc-Hb levels of serumof ob/ob mice treated with a compound according to the presentinvention.

FIGS. 7A and 7B show the assays of liver enzymes in mice 21 days aftertreatment with a compound according to the invention.

FIG. 8 shows glucose uptake in 3T3-L1 cells for a compound of theinvention.

FIG. 9 shows a graph of the comparison of a compound of the inventionwith rosiglitazone for inhibition of LPS-induced TNF production.

FIG. 10 is a graph of the comparison of a compound of the invention withrosiglitazone for inhibition of LPS-induced IL-6 production.

FIG. 11 is a graph of the comparison of a compound of the invention withrosiglitazone for inhibition of LPS-induced IL-1-beta production.

FIGS. 12A and 12B show a comparison of a compound of the invention (FIG.12A) with rosiglitazone (FIG. 12B) for inhibition of LPS-induced COX-2activity.

FIGS. 13A, 13B, 13C and 13D illustrate the suppression ofcollagen-induced arthritis by using a compound according to theinvention.

FIG. 14 illustrates the suppression of experimental allergicencephalomyelitis (EAE) by using a compound according to the invention.

FIG. 15. NF-kB activation in stimulated RAW 264.7 cells.

FIG. 16A. Comparison of percent reduction in blood glucose in db/db miceusing compound 11 and rosiglitazone. 16B. Body weights of the animals.

FIG. 17A. Percent reduction in blood glucose in ob/ob mice usingcompound 11. 17B. Body weights of the animals.

FIG. 18. Serum profile in db/db mice after treatment of 14 days oftreatment.

FIG. 19. Dose response of compound 11 on glucose levels in ob/ob mice.

FIG. 20. A. In vitro glucose uptake measured in differentiated 3T3-L1adipocytes after treatment with increasing concentrations of Compound 11or vehicle. B. Glucose uptake in differentiated 3T3-L1 adipocytesmeasured in the presence of increasing concentrations of insulin in thepresence of vehicle, rosiglitazone or Compound 11.

FIG. 21. In Vivo Antihyperglycemic Activity of Compound 11 in DiabeticAnimals.

FIG. 22. In Vivo Antihyperglycemic Activity of Compound 11 vs.Rosiglitazone in ob/ob mice.

FIG. 23. In Vitro Adipogenic Activity of Compound 11 vs. Rosiglitazonein 3T3-L1 cells. (A) Quantitative measurement of accumulatedtriglyceride. (B) Qualitative assessment of triglyceride accumulation byOil Red O.

FIG. 24. Induction of PPARgamma-Mediated Transactivation of PPRE-LucReporter by Compound 11 and Rosiglitazone.

FIG. 25. Effect of Compound 11 on In Vitro Glycogen Synthesis in HepG2Cells. A. Dose-dependent stimulation of glycogen synthesis from glucoseby Compound 11 in the absence of insulin. B. Time-dependent increase inCompound 11-stimulated glycogen synthesis. C. Cycloheximide blocksglycogen synthesis induced by Compound 11.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

A preferred compound according to formula 1 is 5-(4-(4-(1carbomethoxy-2-(3,5-dimethoxyphenyl)-ethenyl)-phenoxy)-benzyl)-2,4-thiazolidinedione,hereinafter referred to as compound 11. However, it will be appreciatedthat the invention also contemplates the provision and use of othercompounds according to formula 1.

The compounds according to the present invention may be combined with aphysiologically acceptable carrier or vehicle to provide apharmaceutical composition, such as, lyophilized powder in the form oftablet or capsule with various fillers and binders. The effective dosageof a compound in the composition can be widely varied as selected bythose of ordinary skill in the art and may be empirically determined.

As earlier indicated, the compounds of the invention are useful for thetreatment of diabetes, characterized by the presence of elevated bloodglucose levels, that is, hyperglycemic disorders such as diabetesmellitus, including both type I and II diabetes, as well as otherhyperglycemic related disorders such as obesity, increased cholesterol,hyperlipidemia such as hypertriglyceridemia, kidney related disordersand the like. The compounds are also useful for the treatment ofdisorders linked to insulin resistance and/or hyperinsulinemia, whichinclude, in addition to diabetes, hyperandrogenic conditions such aspolycystic ovary syndrome (Ibanez et al., J. Clin Endocrinol Metab,85:3526-30, 2000; Taylor A. E., Obstet Gynecol Clin North Am, 27:583-95,2000), coronary artery disease such as atherosclerosis and vascularrestenosis, and peripheral vascular disease. Additionally, the compoundsof the present invention are also useful for the treatment ofinflammation and immunological diseases that include those mediated bysignaling pathways linked to pro-inflammatory cytokines, such asrheumatoid arthritis and other inflammatory arthritides, multiplesclerosis, inflammatory bowel disease, psoriasis, psoriatic arthritis,ankylosing spondylitis and other spondylarthritides, and contact andatopic dermatitis.

By “treatment”, it is meant that the compounds of the invention areadministered in an amount which is at least sufficient to, for example,reduce the blood glucose level in a patient suffering from hyperglycemicdisorder or to inhibit or prevent the development of pro-inflammatorycytokine or like responses in a patient suffering from inflammatory orimmunological disease. In the case of diabetes, the compound is usuallyadministered in the amount sufficient to reduce the blood glucose level,free fatty acid level, cholesterol level, and the like to an acceptablerange, where an acceptable range means + or −10%, and usually + or −5%of the normal average blood glucose level and like level of the subject,or sufficient to alleviate the symptoms and/or reduce the risk ofcomplications associated with elevated levels of these parameters. Avariety of subjects may be treated with the present compounds to reduceblood glucose levels such as livestock, wild or rare animals, pets, aswell as humans. The compounds may be administered to a subject sufferingfrom hyperglycemic disorder using any convenient administrationtechnique, including intravenous, intradermal, intramuscular,subcutaneous, oral and the like. However, oral daily dosage ispreferred. The dosage delivered to the host will necessarily depend uponthe route by which the compound is delivered, but generally ranges fromabout 0.1-500 mg/kg human body weight or typically from about 1 to 50mg/kg human body weight. Generally similar types of administration anddosages are also contemplated when the compounds of the invention areused to treat inflammatory or immunological disease.

The compounds of this invention may be used in formulations usingacceptable pharmaceutical vehicles for enteral, or parenteral,administration, such as, for example, water, alcohol, gelatin, gumarabic, lactose, amylase, magnesium stearate, talc, vegetable oils,polyalkylene glycol, and the like. The compounds can be formulated insolid form, e.g., as tablets, capsules, drages and suppositories, or inthe liquid form, e.g., solutions, suspensions and emulsions. Thepreparations may also be delivered transdermally or by topicalapplication.

Representative compounds according to the present invention may besynthesized by the methods disclosed below in Schemes 1 through 11,wherein Scheme 1 illustrates the preparation of exemplary compounds 10,11 and 14; Scheme 2 illustrates the preparation of exemplary compounds17 and 18; Scheme 3 illustrates the preparation of exemplary compounds22 and 23; Scheme 6 illustrates the synthesis of exemplary compounds 40,41 and 42; Scheme 7 illustrates the preparation of exemplary compounds46, 47, 49 and 50; Scheme 8 illustrates the synthesis of compound 54;Scheme 9 illustrates the preparation of compounds 58 and 59; and Schemes4, 5, 10 and 11 describe the synthesis methods more generally.

^(a)Reagents and conditions: (a) acetic anhydride, Et₃N, 6 h, 130° C.,47%; (b) MeOH, H₂SO₄, 20 h, reflux, 97%; (c) 4-fluorobenzaldehyde, NaH,DMF, 18 h, 80° C., 77%; (d) 2,4-thiazolidinedione, piperidine, benzoicacid, toluene, 5 h, reflux, 86%; (e) Pd/C(10%), HCOONH₄/AcOH, 48 h,reflux, 49%; (f) NaBH₄, EtOH, 1 h, 25° C., quantitative; (g) PBr₃,CH₂Cl₂, 25° C., 1 h, 99%; (h) BuLi, 2,4-thiazolidinedione, THF, 0° C.,45 min, 15%; (i) aqueous NaOH, MeOH, 15 h, 25° C., 73%.

^(a)Reagents and conditions: (a) Pd/C (10%), H₂, 18 h, 25° C.,quantitative; (b) 4-fluorobenzaldehyde, NaH, DMF, 18 h, 80° C., 69%; (c)2,4-thiazolidinedione, piperidine, benzoic acid, toluene, 2 h, reflux,81%; (d) Pd/C(10%), H₂(60 psi), 34 h, 25° C., 38%.

^(a)Reagents and conditions: (a) acetic anhydride, Et₃N, 24 h, 125° C.,13%; (b) MEOH, H₂SO₄, 18 h, reflux, 35%; (c) 4-fluorobenzaldehyde, NaH,DMF, 18 h, 80° C., 74%; (d) 2,4-thiazolidinedione, piperidine, benzoicacid, toluene, 5 h, reflux, 91%; (e) Pd/C(10%), ammonium formate, aceticacid, 20 h, reflux.

Referring to Scheme 1, the aldehyde 5 and acid 6 may be condensed inacetic anhydride and triethylamine to form the unsaturated acid 7. Afteresterification of the acid to provide compound 8, the phenolic hydroxygroup is formed into an ether 9 with p-fluorobenzaldehyde. The aldehyde9 is then condensed with the thiazolidinedione to provide compound 10and the bond exo to the heterocycle in compound 10 is reduced withhydrogen to form the object compound 11.

The steps in Scheme 1 are generalized in Scheme 4. The general formulas2b, 3b, 4b, 6b, 7b and 8b correspond respectively to formulas 5, 6, 7,9, 10 and 11 in Scheme 1.

In Scheme 5, the general synthesis of the tricyclic products 35 and 36is shown. The aldehyde or ketone 32 is condensed with 33 to form thebicyclic compound 34. The compound 34 is condensed with the heterocyclicdione to form the tricyclic product 35, which can be optionallyhydrogenated to 36.

In Scheme 10, the general synthesis of compounds where R═R′═H is shown.The aldehyde or ketone 62 is condensed with the heterocyclic dione toform the bicyclic compound 63, which can be optionally hydrogenated toform the product 64. Coupling of 64 with optionally substituted aldehydeyields the tricyclic compound 65. Wittig reaction of 65 results in theformation of stilbene derivative 66.

In Scheme 11, the general synthesis of biphenyl products 69 and 70 isshown. Coupling of optionally substituted hydroxyl biphenyl 67 withoptionally substituted aldehyde or ketone yields 68. The aldehyde orketone 68 is condensed with the heterocyclic dione to form the compound69, which can be optionally hydrogenated to form the product 70.

In Formula 1, C₁-C₂₀ linear or branched alkyl means groups such asmethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl,isopentyl, neopentyl, etc. The C₂-C₂₀ linear or branched alkenyl meansunsaturated groups such as ethenyl, propenyl, n-butenyl, isobutenyl,including groups containing multiple sites of unsaturation such as1,3-butadiene, and the like. The halo groups include chloro, fluoro,bromo, iodo. Substituted C₁-C₂₀ linear or branched alkyl or substitutedC₂-C₂₀ linear or branched alkenyl means that the alkyl or alkenyl groupsmay be substituted with groups such as halo, hydroxy, carboxyl, cyano,amino, alkoxy, and the like. The C₁-C₂₀ acylamino or acyloxy group meansan oxygen or amino group bonded to an acyl group (RCO) where R can behydrogen, C₁-C₂₀ linear or branched alkyl or C₂-C₂₀ linear or branchedalkenyl. Alkenyl groups are —C═C—, where R can be hydrogen, C1-C₂₀linear or branched alkyl or C₂-C₂₀ linear or branched alkyl.Alkoxycarbonyl means a group ROCO— where R can be hydrogen, C₁-C₂₀linear or branched alkyl or C₂-C₂₀ linear or branched alkenyl. TheC₁-C₂₀ alkyl carboxyl amino group means a group RCON(R)— where R can beindependently hydrogen, C₁-C₂₀ linear or branched alkyl or C₂-C₂₀ linearor branched alkenyl. Carboxyl is the group H0₂C—, and alkanoyl is thegroup RCO— wherein R is a linear or branched carbon chain. The grouparoyl is Ar—CO— wherein Ar is an aromatic group such as phenyl,naphthyl, substituted phenyl, and the like. Aralkanoyl is the groupAr—R—CO— wherein Ar is a aromatic group such as phenyl, naphthyl,substituted phenyl, etc. and R is a linear branched alkyl chain.

As indicated earlier, the compounds of the invention where a, b or crepresents a double bond may have either the E or Z configuration. Onthe other hand, when a, b or C is absent, i.e. a single bond is present,the resulting compounds may be R— and/or S-stereoisomers. The inventioncontemplates racemic mixtures of such stereoisomers as well as theindividual, separated stereoisomers. The individual stereoisomers may beobtained by the use of an optically active resolving agent.Alternatively, a desired enantiomer may be obtained by stereospecificsynthesis using an optically pure starting material of knownconfiguration.

The preparation of compound 11, i.e.5-(4-(4-(1-carbomethoxy)-2-(3,5-dimethoxyphenyl)-ethenyl)-phenoxy)-benzyl)-2,4-thiazolidinedione (also known as3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester), is described below with reference to Scheme 1.

Perkin condensation of 3,5-dimethoxybenzaldehyde 5 with4-hydroxyphenylacetic acid 6 yielded the alpha-phenyl substitutedcinnamic acid 7 exclusively as E-isomer. The geometry of the double bondwas confirmed by ¹HNMR comparison with the reported compound (Pettit etal, J Nat Prod 51:517-27, 1998). Esterification of 7 followed bycondensation with 4-fluorobenzaldehyde yielded 9. Knovenagelcondensation of aldehyde 9 with 2,4-thiazolidinedione in the presence ofpiperidinium benzoate with azeotropic removal of water gave a good yieldof 10.

A major challenge was selective hydrogenation of the double bonds inorder to produce compounds 11, 17 and 18. Reduction of 10 withmagnesium/methanol was non-selective and yielded a mixture of products.Zinc-acetic acid reduction gave a mixture of polar product.Hydrogenation with 10% palladium on carbon as catalyst in 1,4-dioxaneyielded a mixture of 11 and 18 in a ratio of 6:4. Separation of thecompounds from this mixture was only possible by reverse phasechromatography on C-18 silica. These problems were overcome in severalways. Hydrogenation of 10 using ammonium formate as hydrogen donor inthe presence of palladium catalyst (Hudlicky, ACS Monograph 188:46-7,1996; Ram and Ehrenkaufer, Synthesis 91-5, 1988) produced minimalamounts of the over-reduced product 18, and isolation of 11 in highpurity was possible by repeated crystallization from methanol. In apreferred variation of this approach, platinum catalyst was substitutedfor palladium, and the crude product was recrystallized fromdichloromethane; with these modifications both the amount of catalystrequired and the reaction time were significantly reduced, while theoverall yield was considerably improved. In an another attempt to make11, the aldehyde 9 was reduced to alcohol 12 which upon treatment withPBr₃ yielded the bromo compound 13 in high yield. The bromo compound wascondensed with 2,4-thiazolidinedione anion generated by BuLi to yield 11in low yield.

It was difficult to synthesize 18 in good yield from either 10 or 11 bypalladium-catalyzed hydrogenation due to poisoning of the catalyst bythe 2,4-thiazolidinedione moiety in the molecule; the resulting mixturescontained 18 as a minor product. To solve this problem (as shown inScheme 2), 8 was first reduced, by using 10% palladium on carbon ascatalyst, to 15 quantitatively followed by coupling with4-fluorobenzaldehyde and 2,4-thiazolidinedione to furnish 17 in goodyield. Reduction of 17 with palladium on carbon catalyst for a longerperiod of time and catalyst renewal half-way through the reaction,followed by chromatographic purification over C-18 reverse phase silicagel, produced 18 in moderate yield.

The synthetic strategy adopted to prepare 23, the corresponding Z-isomerof 11, is outlined in Scheme 3. Prolonged heating of 7 with aceticanhydride and triethylamine (Kessar et al, Indian J Chem 20B:1-3, 1981)yielded the corresponding Z-isomer 19 in 13% yield. Interestingly, thereaction of 2,4-thiazolidinedione with 21, in order to produce 22,showed minimal isomerization of the cinnamic acid double bond andresulted in a mixture of E- and Z-isomers in a ratio of 1:7respectively. Reduction was carried out without further purification andthe final product was purified by preparative HPLC to yield 23.

EXAMPLE 1

General Methods. Melting points were measured on a Mel-Temp meltingpoint apparatus and are uncorrected. The ¹H NMR and ¹³C NMR spectra wererecorded on a JEOL Eclipse (400 MHz) or Nicolet NT 36 (360 MHz)spectrometer and are reported as parts per million (ppm) downfield fromTMS. The infrared spectra were recorded on a Nicolet Impact 410 FT-IRspectrophotometer. The mass spectra were recorded on Fison VG PlatformII of HP 1100 MDS 1964A mass spectrophotometer. UV spectra were recordedon a Beckman DU650 spectrophotometer. TLC was done on Merck silica gelF₂₅₄ precoated plates. The silica gel used for column chromatography was‘Baker’ silica gel (40 μm) for flash chromatography.

3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid (7). To amixture of 3,5-dimethoxybenzaldehyde, 5, (500 g, 3.0 mol) and4-hydroxyphenyl acetic acid, 6, (457 g, 3.0 mol) was added aceticanhydride (1.0 L, 10.60 mole) and triethylamine (420 mL, 3.0 mol). Afterstirring at 130-140° C. for 6 h, the mixture was cooled to roomtemperature. Concentrated HCl (1 L) was added to the reaction mixtureslowly over 50 min while keeping the temperature between 20-30° C. Thelight yellow precipitate obtained was filtered and washed with water.The solid was dissolved in 3N NaOH (5 L) and stirred for 1 h andfiltered. The filtrate was acidified to pH 1 with concentrated HCl whilemaintaining a temperature at 25-30° C. The precipitated product wasfiltered and washed with water to give crude product that wasrecrystallized from MeOH—H₂O and dried at 40° C. for 6 h to yield 7 (428g, 47%): mp 225-227° C. (lit. 226-228° C.)¹⁷; ¹HNMR (360 MHz, DMSO-d₆)δ12.48 (br s, 1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=8.0 Hz, 2H),6.76 (d, J=8.0 Hz, 2H), 6.35 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H),3.56 (s, 6H); MS (EI) m/z 299[M]⁻.

3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid methyl ester(8). Methanol (3.0 L) was added to a thoroughly dried 7 (427.5 g, 1.42mol) under argon. To this stirred suspension concentrated sulfuric acid(100 mL) was added and heated at reflux for 20 h under nitrogen.Methanol was evaporated under reduced pressure at 30° C. The residue wastaken up in ethyl acetate (3.0 L) and washed with water (2×1.0 L),saturated aqueous Na HCO₃ (2×1.0 L), brine (2×1.0 L). The organic layerwas dried on anhydrous magnesium sulfate, filtered and the solvent wasevaporated. The residue obtained was dried thoroughly under high vacuumas white solid, (433.6 g 97%): mp 106-108° C.; ¹HNMR(360 MHz, CDCl₃): δ7.72 (s, 1H), 7.06 (d, J=7.9 Hz, 2H), 6.77 (d, J=7.9 Hz, 2H), 6.33 (t,J=2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 2H), 5.74 (s, 1H), 3.81 (s, 3H), 3.60(s, 6H); MS (EI) m/z 315[M]⁺.

3-(3,5-Dimethoxyphenyl)-2-[4-(4-formylphenoxy)-phenyl]-acrylic acidmethyl ester (9). Under argon, 8 (433.0 g, 1.37 mol) was dissolved indry DMF (1.6 L) and to this sodium hydride (60.4 g, 1.51 mol) was added.To the resulting orange solution 4-fluorobenzaldehyde (185.0 mL, 1.71mol) was added and heated at 80° C. for 18 h. The reaction mixture wascooled to room temperature, diluted with ethyl acetate (3.0 L) andextracted with water (3×1.0 L), then brine (1×1.0 L). The organic layerwas dried over anhydrous sodium sulfate, filtered and solvent wasevaporated. The residue was suspended in methanol (3.0 L) and stirredovernight. Solid was filtered and dried under vacuum at 40° C. to yield9 as pale yellow solid (445 g, 77%): mp 108-110° C. ¹HNMR(360 MHz,CDCl₃) δ 9.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 7.28 (d,J=8.6 Hz, 2H), 7.11 (overlapped d, J=9.0 Hz, 2H), 7.08 (overlapped d,J=9.0 Hz, 2H), 6.36 (t, J=2.2 Hz, 1H), 6.25 (d, J=2.2 Hz, 2H), 3.83 (s,3H), 3.63 (s, 6H).

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (10). To a stirred suspension of 9 (352 g, 0.82 mol)in anhydrous toluene (2.5 L), 2,4-thiazolidinedione (98.6 g, 0.84 mol),benzoic acid (134 g, 1.10 mol) and piperidine (107.4 g, 1.26 mol) wasadded sequentially and heated at reflux temperature with continuousremoval of water with the help of Dean-Stark apparatus for 5 h. Toluene(1.0 L) was removed from the reaction mixture and cooled overnight at 4°C. Solid separated was filtered and mother liquor was evaporated todryness under reduced pressure. The residue obtained was re-dissolved ina mixture of MeOH—diethylether (1:1, 3.0 L). On standing overnight at 4°C., the solution yielded more solids. Solid from both the lots werecombined and dried overnight in vacuum oven at 40° C. to give 10 asyellow solid (362.5 g, 86%): mp 106-108° C.; mp 225-226° C.; ¹H NMR (360MHz, DMSO-d₆):

12.53 (br s, 1H), 7.78 (s,1H), 7.73 (s,1H), 7.63 (d, J=9.2 Hz, 2H), 7.25(d, J=9.2 Hz, 2H), 7.13 (overlapped d, J=8.3 Hz, 2H), 7.11 (overlappedd, J=8.6 Hz, 2H), 6.42 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 3.73(s, 3H), and 3.59 (s,6H); MS (EI) m/z 518[M]⁺.

5-(4-(4-(1-carbomethoxy-2-(3,5-dimethoxyphenyl)-ethenyl)-phenoxy)-benzyl)-2,4-thiazolidinedione,also called3-(3,5-dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (compound 11). Compound 10 (30 g, 58 mmol) wasdissolved in warm dioxane (900 mL), transferred to a 2 L hydrogenationbottle and 10% Pd—C (˜50% water, 15 g) was added to this andhydrogenated in a Parr hydrogenator at 60 psi for 24 h. Following thisperiod, an additional 15 g Pd—C was added and hydrogenation was allowedto continue for another 24 h. Catalyst was filtered through a bed ofCelite and solvent was evaporated. The residue was taken up inacetonitrile (500 mL) and adsorbed on C-18 silica (50 g). The adsorbedmaterial was placed on the top of a column containing C-18 reverse phasesilica gel (400). Column was eluted with CH₃CN in H₂O (45%, 2 L), CH₃CNin H₂O (50%, 2 L), CH₃CN in H₂O (55%, 2 L) to elute the undesiredfractions. Fractions were collected with the start of 60% CH₃CN in H₂Oelution for the desired compound. Fractions were mixed on the basis oftheir HPLC purity. Acetonitrile was evaporated under reduced pressure.Water was removed by lyophilization. Yield: 12 g (40%). White solid;m.p. 126-128° C. ¹H NMR (DMSO-d₆) δ 12.01 (br, 1 H), 7.73 (s, 1 H), 7.28(d, J=8.6 Hz, 2H), 7.19(d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 6.96(d, J=8.6 Hz, 2H), 6.40 (t, J=2.2 Hz, 1 H), 6.27 (d, J=2.2 Hz, 2H), 4.92(dd, J=9.2 and 4.4 Hz, 1 H), 3.73 (s, 3H), 3.57 (s, 6H), 3.37 (dd,J=14.8 and 4.3 Hz, 1 H) and 3.12 (dd, J=14.8 and 9.4 Hz, 1 H); IR (KBr)ν_(max) 3200, 2950, 2850, 1700, 1600, 1500, 1350, 1150, and 850 cm⁻¹;EIMS:m/z, 518, [M-H]⁻265, 249, and 113.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (11). To a solution of 10 (599 g, 1.16 mol) in glacialacetic acid (11.5 L), ammonium formate (4.0 kg, 62.9 mol) was added andstirred for 30 min. A slurry of Pd on carbon (10%, dry, 300 g) inglacial acetic acid (500 mL) was added to the flask (caution: in a largescale reaction exothermicity may be a problem; rigorous exclusion ofoxygen is desirable) and heated at 120° C. for 24 h followed by stirringat room temperature for 48 h. The resulting mixture was filtered througha bed of Celite®. The filtrate was poured slowly into vigorously stirredwater (12 L) and the separated solid was filtered and dried. Resultingsolid was purified by slurring twice in hot methanol followed by oncefrom ethanol to yield pure 11 as white solid (296 g, 49.2%): mp 126-128°C.; ¹H NMR (400 MHz, DMSO-d₆)

12.01 (br s, 1H), 7.73 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.19 (d,J=8.6Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.40 (t,J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 4.92(dd, J=9.2 and 4.4 Hz, 1H),3.73 (s, 3H), 3.57 (s, 6H), 3.37 (dd, J=14.8 and 4.3 Hz, 1H) and 3.12(dd, J=14.8 and 9.4 Hz, 1H); IR (KBr) ν_(max) 3200, 2950, 2850, 1700,1600, 1500, 1350, 1150, and 850 cm⁻¹; MS (EI) m/z 518[M-H]⁻, 265, 249,and 113.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (11). Compound 10 (20 g, 38.6 mmol), ammonium formate(150 g, 2.38 mol), 10% Pt/C (dry, 4 g) and acetic acid (660 mL) werecombined into a round bottom flask equipped with reflux condenser,thermometer and mechanical stirrer. The reactor was evacuated and purgedthree times with nitrogen then, heated to a steady reflux (ca. 124° C).Reaction was completed within 15 h and allowed to cool with stirring toambient room temperature. After cooling, the mixture was filtered thougha pad of Celite® (5 g) and the filter pad washed with fresh acetic acid(2×100 mL). The mother liquor and washes were combined and concentrated.The residue was then diluted with dichloromethane (400 mL), and thecombined organics were extracted twice with water (400 mL) and 5%bicarbonate (400 mL). The organic portion was then dried and pouredthrough silica gel (30 g) and washed with dichloromethane (2×100 mL).The washes were combined and concentrated. The residue was diluted withethanol, allowed to cool to 60° C. and seed crystals were added. Thisslurry was stirred at 50° C. for about 30 min then allowed to cool toambient room temperature to yield compound 11 (12.85 g, 64%) with anHPLC assay of 98.1%.

3-(3,5-Dimethoxyphenyl)-2[4-(4-hydroxymethylphenoxy)-phenyl]-acrylicacid methyl ester (12). Compound 9 (5.0 g, 11.9 mmol) was suspended inanhydrous ethanol (60 mL) at room temperature and sodium borohydride(0.23 g, 6.1 mmol) was added with efficient stirring. Reaction wascomplete in 1 h, solvent was evaporated and the residue was dissolved inethyl acetate. The organic layer was extracted with water (50 mL), brine(25 mL), dried on anhydrous magnesium sulfate, filtered and solvent wasevaporated to yield the title compound 12 as white solid (5.1 g, 100%):mp 93-95° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.35 (d, J=8.8Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4Hz, 2H), 6.41 (t, J=2.4 Hz, 1H), 6.29 (d, J=2.0 Hz, 2H), 5.18 (t, J=6.4Hz, 1H), 4.49 (d, J=4.8 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 6H); MS (EI) m/z315[M]⁺.

2-[4-(4-Bromomethylphenoxy)-phenyl]-3-(3,5-dimethoxyphenyl)-acrylic acidmethyl ester (13). A solution of PBr₃ (4.8 mL of 1.0 M in CH₂Cl₂) wasadded dropwise to 12 (5.0 g, 11.9 mmol) dissolved in CH₂Cl₂ (20 mL) attemperature with good stirring. After 1 h, the solution was extractedwith water (2×60 mL) and brine (20 mL). The organic phase was dried overanhydrous magnesium sulfate, filtered through a small bed of silica gel(20 g) and solvent was evaporated. The resulting tacky syrup was driedunder high vacuum for 48 h at room temperature to yield the titlecompound (5.7 g, 99%): mp 79-81° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.73(s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.42 (t, J=2.4 Hz, 1H), 6.28 (d, J=2.0Hz, 2H), 4.73 (d, J=4.8 Hz, 2H), 3.68 (s, 3H), 3.58 (s, 6H); Anal.(C₂₅H₂₃BrO₅) C: calculated, 61.12; found, 62.26; H: calculated 4.80;found 4.88.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (11). 2,4-Thiazolidinedione (2.83 g, 24.2 mmol) wasdissolved in dry THF (170 mL) and cooled to 0° C. under argon.Butyllithium (1.6 M in hexanes, 30 mL, 48.0 mmol) was added dropwise.Stirring continued for 0.5 h at 0° C. Under argon, 13 (5.7 g, 11.8 mmol)was dissolved in dry THF (30 mL) and was added rapidly via syringe tothe above suspension with rapid stirring. The temperature was maintainedat 0° C. for 45 min before quenching with aqueous HCl (5%, 40 mL).Additional H₂O (40 mL) was added and extracted with ethyl acetate (3×30mL). Organic layers were combined, washed with brine, dried overanhydrous magnesium sulfate, filtered and the solvent was evaporated.Flash chromatography over silica gel using hexanes-ethyl acetate (3:2)as eluting solvent yielded the title compound, 11, (0.93 g, 15%). Themelting point and ¹H NMR of compound 11 made by this method wereidentical to those for compound 11 produced by the synthetic routestarting from compound 10 described above.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenylacrylic acid (14). To a stirred, cooled below 10° C., suspension of 11(10 g, 19.27 mmol) in methanol (50 mL), aqueous sodium hydroxide (2N,33.7 mL, 67.4 mmol) was added and stirred for 15 h at room temperature.The resulting pale yellow solution was cooled to 10° C. and acidifiedwith aqueous HCl (5%, 115 mL). Solid separated was filtered and washedwith water (3×30 mL), recrystallized from ethanol to give 14 as whitesolid (7.14 g, 73%): mp 138-140° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.69(s, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.41 (t, J=2.4 Hz, 1H), 6.28 (d, J=2.4Hz, 2H), 4.92 (dd, J=9.2 and 4.4 Hz, 1H), 3.58 (s, 6H), 3.38 (dd, J=14.0and 4.0 Hz, 1H) and 3.13 (dd, J=14.4 and 9.2 Hz, 1H); MS (EI) m/z506[M]⁺.

3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-propionic acid methyl ester(15). To a suspension of 8 (6.28 g, 20.0 mmol) in ethanol (200 mL)palladium on carbon (10%, wet, 0.63 g) was added and stirred under H₂ atatmospheric pressure at room temperature for 18 h. Catalyst was filteredthrough a bed of Celite® and solvent was evaporated under reducedpressure to yield 15 as white solid (6.32 g, 100%): mp 63-65° C.; ¹HNMR(400 MHz, DMSO-d₆): δ 7.15 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H),6.29 (t, J=2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 2H), 3.78(t, J=8.7 Hz, 1H),3.72(s, 6H), 3.62(s, 3H), 3.31(dd, J=13.5 and 8.4 Hz, 1H), 2.93(dd,J=13.5 and 6.9 Hz, 1H); MS (EI) m/z 317[M]⁺.

3-(3,5-Dimethoxyphenyl)-2-[4-(4-formylphenoxy)-phenyl]-propionic acidmethyl ester (16). To a suspension of sodium hydride (60% in oil, 0.25g, 6.3 mmol) in DMF (2 mL) under argon, 15 (2.0 g, 6.3 mmol) in dry DMF(3 mL) was added. To the resulting yellow solution, 4-fluorobenzaldehyde(0.68 mL, 6.3 mmol) was added and heated at 80° C. for 18 h. Thereaction mixture was cooled to room temperature, water (20 mL) was addedand extracted with ethyl acetate (3×50 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and solvent was evaporated. Anethyl acetate solution of crude product was filtered through a small bedof silica gel to yield 16 (1.83 g, 69%) as oil: ¹HNMR(400 MHz, DMSO-d₆):δ 9.91 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.04 (d,J=5.4 Hz, 2H), 7.01 (d, J=5.4 Hz, 2H), 6.30 (t, J=2.1 Hz, 1H), 6.25 (d,J=2.1 Hz, 2H), 3.86 (t, J=7.8 Hz, 1 Hz), 3.76 (s, 6H), 3.66 (s, 3H),3.36 (dd, J=12.6 and 8.1 Hz, 1H), 2.97 (dd, J=13.5 and 7.5 Hz, 1H); MS(EI) m/z 421 [M]⁺.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionicacid methyl ester (17). To a stirred suspension of 16 (1.81 g, 4.3 mmol)in anhydrous toluene (25 mL), 2,4-thiazolidinedione (0.56 g, 4.74 mmol),benzoic acid (0.68 g, 5.60 mmol) and piperidine (0.60 mL, 6.03 mmol) wasadded sequentially and heated at reflux temperature with continuousremoval of water using a Dean-Stark apparatus for 2 h. Solvent wasevaporated to dryness under reduced pressure. The residue obtained waspurified by silica gel chromatography, eluted with hexane-ethyl acetate(1:1) to yield 17 (1.82 g, 81%): mp 104-106° C.; ¹H NMR (400 MHz,DMSO-d₆)

12.53 (br s, 1H), 7.76 (s,1H), 7.60 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7Hz, 2H), 7.07 (d, J=4.8 Hz, 2H), 7.03 (d, J=4.8 Hz, 2H), 6.33-6.28 (m,3H), 4.01 (t, J=7.5 Hz, 1 Hz), 3.66 (s, 6H), 3.56 (s, 3H), 3.22 (dd,J=13.8 and 8.4 Hz, 1H), 2.90 (dd, J=13.5 and 7.2 Hz, 1H); MS (EI) m/z520[M]⁺; Anal. (C₂₈H₂₅NO₇S) C: calculated, 64.73; found, 65.89; H:calculated, 4.85; found, 5.08, N: calculated, 2.70; found, 2.56.

3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionicacid methyl ester (18). 17 (1.6 g, 3.08 mmol) was dissolved in dioxane(45 mL), transferred in a hydrogenation bottle and Pd on carbon (10%,1.0 g) was added. Hydrogenation was done at 65 psi for 34 h. Followingthis period, additional Pd on carbon (10%, 0.6 g) was added andhydrogenation was allowed to continue for another 18 h. Catalyst wasfiltered through a bed of Celite® and solvent was evaporated. Theresidue was purified by column chromatography on reverse phase silicagel (C-18) using acetonitrile-water (1:1) mixture to elute 18 as whitesolid (0.60 g, 38%): mp 125-128° C.; ¹H NMR (400 MHz, DMSO-d₆)

12.04 (br s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.92(d, J=8.6 Hz, 4H), 6.30 (d, J=2.0 Hz, 2H), 6.29 (t, J=2.0 Hz, 1H), 4.90(dd, J=9.2 and 4.4 Hz, 1H), 3.98 (t, J=8.0 Hz, 1H), 3.67 (s, 6H), 3.56(s, 3H), 3.37 (dd, J=13.6 and 4.0 Hz, 1H), 3.21 (dd, J=14.0 and 8.8 Hz,1H); 3.11 (dd, J=14.0 and 9.2 Hz, 1H) and 2.90 (dd, J=13.6 and 7.6 Hz,1H); MS (EI) m/z 522[M]⁺.

Z-3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid (19).E-3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid, 7 (10.0 g,33.3 mmol) was dissolved in a mixture of acetic anhydride (40 mL, 0.42mole) and triethylamine (40 mL, 0.29 mole) and heated at 125° C. for 24h. The mixture was cooled to room temperature. Ethyl acetate (150 mL)was added, further cooled to 5° C., acidified with concentrated HCl (30mL) and stirred at this temperature for 90 min. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (100mL). The combined organic layers were washed with water (2×50 mL) andextracted with aqueous NaOH (5M, 3×70 mL). The aqueous alkaline layerwas acidified with glacial acetic acid (65 mL) to pH 5.2 and stirred at0° C. for 30 min. Solid that separated was filtered and mother liquorwas acidified with concentrated HCl (90 mL) and stirred at 5° C. for 1h. Solid that separated was filtered, washed with cold water (2×50 mL)and dried at 45° C. for 6 h to yield, 19, (1.3 g, 13%): mp 135-137° C.;¹HNMR (400 MHz, DMSO-d₆) δ 13.28 (br, 1H), 9.70 (br, 1H), 7.32 (d,J=10.4 Hz, 2H), 6.81(s, 1H, overlapped), 6.79 (d, J=9.7 Hz, 2H), 6.67(d, J=2.5 Hz, 2H), 6.64 (t, J=2.5 Hz, 1H), and 3.73 (s, 6H); MS (EI) m/z299[M]⁻.

Z-3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid methyl ester(20). Concentrated sulfuric acid (10 drops) was added to a stirredmethanol suspension of thoroughly dried 19 (0.60 g, 2.0 mmol) underargon and heated at reflux for 18 h. Methanol was evaporated underreduced pressure, residue was taken up in ethyl acetate (20 mL) andwashed with water (20 mL), saturated aqueous Na HCO₃ (10 mL) and brine(10 mL). The organic layer was dried on anhydrous magnesium sulfate,filtered and the solvent was evaporated. The crude product obtained waspurified by chromatography over silica gel and eluted with hexane-ethylacetate (7:3) to yield 20 as white solid (0.24 g, 35%): ¹HNMR (400 MHz,CDCl₃) δ 7.26 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J=8.4 Hz, 2H),6.45 (d, J=2.0 Hz, 2H), 6.34 (t, J=2.0 Hz, 1H), 4.97 (s, 1H), 3.73(s,3H), 3.72(s, 6H).

Z-3-(3,5-Dimethoxyphenyl)-2-[4-(4-formylphenoxy)-phenyl]-acrylic acidmethyl ester (21). Under argon, 20 (0.60 g, 1.9 mmol) was dissolved indry DMF (4 mL) and to this sodium hydride (60% in oil, 0.09 g, 2.28mmol) was added. To the resulting orange solution, 4-fluorobenzaldehyde(0.25 mL, 2.28 mmol) was added and heated at 80° C. for 18 h. Thereaction mixture was cooled to room temperature, water (10 mL) was addedand the mixture was extracted with ethyl acetate (3×20 mL). The crudeproduct obtained after evaporation was purified by chromatography oversilica gel and elution with a mixture of hexane-ethyl acetate (4:1) toyield 21 as white solid (0.59 g, 74%): ¹HNMR(400 MHz, CDCl₃) δ 9.93 (s,1H), 7.86 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.10 (overlapped d,J=8.8 Hz, 2H), 7.08 (overlapped d, J=8.8 Hz, 2H), 6.96 (s, 1H), 6.53(dd, J=2.8 Hz, 2H), 6.43 (t, J=2.0 Hz, 1H), 3.80(s, 3H), 3.79 (s, 6H).

Z-3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (22). To a stirred suspension of 21 (0.53 g, 1.3 mmol)in anhydrous toluene (10 mL), 2,4-thiazolidinedione (0.15 g, 1.30 mmol),benzoic acid (0.21 g, 1.69 mmol) and piperidine (0.19 g, 1.95 mmol) wereadded sequentially and the mixture was heated at reflux temperature withcontinuous removal of water using a Dean-Stark apparatus for 5 h.Toluene was evaporated and the residue was chromatographed over silicagel and eluted with hexane-ethyl acetate (1:1) to yield a mixture of 22and 10 (0.60 g, 91%) in a ratio of 7:1 on the basis of proton NMRanalysis: ¹H NMR (400 MHz, DMSO-d₆):

12.53 (br s, 1H), 7.79 (s,1H), 7.65 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.18 (overlapped d, J=8.8 Hz, 2H), 7.16 (overlapped d, J=8.8Hz, 2H), 7.17 (overlapped s,1H), 6.57 (d, J=2.0 Hz, 2H), 6.50 (t, J=2.0Hz, 1H), 3.79 (s, 3H), and 3.75 (s, 6H).

Z-3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (23). To a solution of 22 (0.60 g, 1.6 mmol) in aceticacid (15 mL) was added Pd on carbon (10%, 300 mg) and ammonium formate(4.3 g, 55.8 mmol) (caution: in a large scale reaction exothermicity maybe a problem; rigorous exclusion of oxygen is desirable) and heated at120° C. for 20 h. Catalyst was filtered through a bed of Celite® andacetic acid was evaporated under reduced pressure. Water (50 mL) wasadded to the residue and solid separated was filtered. Pure Z-isomer wasisolated by preparative HPLC using Intersil ODS-3 preparative column(250×4.6 mm, 5 μm) running at a rate of 15 mL per minute usingmethanol:acetonitrile:water (3:3:2) containing formic acid (0.05%): mp65-66° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s, 1H), 7.48 (d, J=9.2Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.13(s, 1H), 7.03 (overlapped d, J=8.8Hz, 2H), 7.01 (overlapped d, J=8.4 Hz, 2H), 6.56 (d, J=2.0 Hz, 2H), 6.49(t, J=2.0 Hz, 1H), 4.90(dd, J=9.2 and 4.4 Hz, 1H), 3.77 (s, 3H), 3.75(s, 6H), 3.38 (dd, J=14.8 and 4.8 Hz, 1H) and 3.13 (dd, J=14.4 and 9.2Hz, 1H); MS (I) m/z 300[M]⁺.

Referring to the drawings, compound 11 was administered in a single oraldose (50 mg/kg body weight) for 15 days to db/db male mice as shown inFIG. 1A. A substantial reduction in blood glucose level was observed.There was no increase in body weight in the treatment group as comparedto the control treated with the vehicle without the active ingredient,FIG. 1B.

The compound was orally administered to ob/ob mice with a single oraldose (50 mg/kg body weight). As shown in FIG. 2A, there was a 62% dropin blood glucose level and, similar to db/db mice, there was nosignificant increase in body weight between the control and thetreatment groups as shown in FIG. 2B. This is in contrast to treatmentof diabetic animals by thiazolidinedione type compounds which are knownto be associated with increase in body weight. See Okuno et al., J.Clin. Invest., 101, 1354-1361 (1998) and Yoshioka et al., Metabolism,42, 75-80 (1993). By stopping treatment after day 15 in both models,there was shown an increase in glucose level as depicted in FIGS. 3A and3B. The time course of the drug effect is shown in FIG. 4. Oraladministration of a single dose of the compound in db/db mice waseffective for 24 hours and beyond.

The triglyceride levels were also measured. Triglycerides, which areesters of fatty acids and glycerol, do not freely circulate in plasmabut are bound to proteins and transported as macromolecular complexescalled lipoproteins. The triglycerides were measured by the enzymaticmethod described by McGowan et al., Clin Chem 29:538-42, 1983, with amodification to determine the triglyceride levels in db/db and ob/obmice. There was shown a 24% drop in triglyceride levels in db/db mice(FIG. 5A) after 15 days of treatment with the compound and in ob/obmice, a 65% decrease in triglyceride as compared to the control (FIG.6B) after treatment for 10 days.

The free fatty acids (FFA) were enzymatically measured using coenzyme Ain the presence of acyl CoA synthase (Wako Chemicals USA). The freefatty acid levels in db/db and ob/ob mice treated with the compound weresignificantly lower compared to the control animals. A 34% drop in FFAlevels in db/db mice (FIG. 5B) was shown after 15 days of treatment withthe compound. In ob/ob mice, after 10 days of treatment, a lowering of33% of FFA was shown compared to the control (FIG. 6C).

The percentage of glycohemoglobin (GHb) in blood reflects the averageblood glucose concentration. It is a measure of overall diabetic controland can be use to monitor the average blood glucose levels. Theglycosylation of hemoglobin occurs continuously in the red blood cells.But since the reaction is non-enzymatic and irreversible, theconcentration of glycohemoglobin in a cell reflects the average bloodglucose levels seen by the cell during its life. An assay was conductedusing affinity chromatography with boronate as described by Abraham etal., J. Lab. Clin. Med., 102, 187 (1983). There is a 0.7% drop in theGHb level in db/db mice (FIG. 5C) after 15 days of treatment with thecompound and in ob/ob mice after 14 days of treatment, there is 1.3%decrease (FIG. 6D) in the GHb level compared to the control. The bloodinsulin level was measured by ELISA following a standard protocol. A 58%drop of serum insulin in ob/ob mice (FIG. 6A) was shown after 10 days oftreatment with the compound, thus, demonstrating its ability to act asan insulin sensitizer.

Obesity is considered a significant risk factor for various adultdiseases such as diabetes and cardiac disease. Leptin, an obese geneproduct, has been identified from the investigation of ob/ob mice, wherethe leptin is lacking because of a mutation in that gene (Zhiang et al.,Nature, 372, 425 (1994). Leptin is a protein of about 16 kDa, which isexpressed in adipose tissue, and which promotes weight loss bysuppressing appetite and stimulating metabolism. It is currentlybelieved that leptin plays a key role in the obesity syndrome. In thedb/db mice according to the experiment, the leptin level was measured byan ELISA, following a standard protocol. After 15 days of treatment withthe compound, there is a 23°/a increase (FIG. 5D) in the serum leptinlevel compared to the control group.

The liver enzymes glutamic oxalacetic transaminase/aspartateaminotransferase (AST/GOT) and glutamic pyruvic transaminase/alanineaminotransferase (ALT/GPT) were assayed in the sera of ob/ob mice after21 days of treatment (orally, 50 mg/kg) of the test compound. The testwas also conducted using troglitazone. These enzyme levels are found toelevate in several kinds of hepatic disorders or liver necrosis. In FIG.7A, the AST level in the mice was not elevated compared to untreatedmice or to mice treated with troglitazone. Similarly, FIG. 7B shows thatthe ALT level did not elevate compared to untreated mice or mice treatedwith troglitazone.

Referring to FIG. 8 glucose uptake in 3T3-L1 differentiated adipocyteswas measured after treatment with the test compound. The assay wasconducted according to the method of Tafuri, Endocrinology, 137,4706-4712 (1996). The serum-starved cells were treated with the testcompound for 48 hours at different concentrations, then washed andincubated in glucose-free media for 30 minutes at 37° C. Then¹⁴C-deoxyglucose was added and uptake was monitored for 30 minutes underincubation. After washing, the cells were lysed (0.1% SIDS) and counted.As shown in FIG. 8, there is a 3.5 to 4-fold increase in glucose uptakeat the indicated concentrations of the test compound with respect tobasal levels.

Referring to FIG. 9, RAW cells were preincubated with either compound 11or rosiglitazone (0.1, 1, 10, 50 or 100 pM) for 1 hour at 37° C. inRPMI-1640 containing 10% FBS. After 1 hour, LIPS (0.1 pg/ml) was addedand cells were incubated an additional 6 hours. Cell supernatant wasthen collected, aliquoted and frozen at −70° C., and an aliquot used todetermine TNF-alpha concentration by ELISA. Compound 11 was a betterinhibitor of TNF-alpha than rosiglitazone.

Referring to FIG. 10, RAW cells were preincubated with either compound11 or rosiglitazone (0.1, 1, 10, 50 or 100 pM) for 1 hour at 37° C. inRPMI-1640 containing 10% FBS. After 1 hour LIPS (0.1 pg/ml) was addedand cells were incubated an additional 6 hours. Cell supernatant wasthen collected, aliquoted and frozen at −70° C., and an aliquot used todetermine the concentration of IL-6 by ELISA. Compound 11 was a betterinhibitor of IL-6 than rosiglitazone.

Referring to FIG. 11, RAW cells were preincubated with either compound11 or rosiglitazone (0.1, 1, 10, 50 or 100 pM) for 1 hour at 37° C. inRPM 1-1640 containing 10% FIBS. After 1 hour LPS (0.1 pg/mL) was addedand cells were incubated an additional 6 hours. Cell supernatant wasthen collected, aliquoted and frozen at −70° C., and an aliquot used todetermine the concentration of IL-1-beta by ELISA. Compound 11 inhibitedIL-1-beta better than rosiglitazone.

Referring to FIGS. 12A AND 12B, RAW cells were preincubated with eithercompound 11 (12A) or rosiglitazone (12B) (0.1, 1.0, 10, 50 or 100 μM)for 1 hour at 37° C. in RPMI-1640 containing 10% FIBS. After 1 hour LPS(0.1 pg/mL) was added and cells were incubated an additional 6 hours.Cell supernatant was then collected, aliquoted and frozen at −70° C.,and aliquots used to determine COX-2 and COX-1 activity. Compound 11,but not rosiglitazone, inhibited the activity of COX-2 (as measured byPGE2 production in a 50 μl sample). Neither compound inhibited COX-1activity.

The transcription factor NF-kappaB coordinates the activation of manygenes involved in the response to pro-inflammatory cytokines, and,therefore, plays a key role in the development of inflammatory diseases.NF-kappaB is activated by phosphorylation of the inhibitory proteinIkappaB. To examine the effect of compound 11 on the LPS-stimulatedphosphorylation of IkappaB, RAW 264.7 cells were preincubated withvehicle only, 15-deoxy-Δ^(12,14)-prostaglandin J2 (15dPGJ₂) (3 pM) as apositive control, compound 11 (3, 10 or 30 pM), or rosiglitazone (3, 10or 30 μM) for 1 hr. at 37° C. Then, cells were treated with or withoutLPS (10 μg/mL) plus IFN-gamma (10 U/mL) for 5 min. or 15 min. at 37° C.Cells were then lysed, and the cell lysates (27 μg/lane) were separatedby electrophoresis on a 4-20% polyacrylamnide gel, blotted onto anitrocellulose membrane and probed with anti-phospho-IkappaB antibody.The results revealed that compound 11, but not rosiglitazone, exhibiteddose-dependent inhibition of the phosphorylation of IkappaB.

To further confirm the ability of Compound 11 to inhibit the activationof NF-kB, the production of free p65 (activated) NF-kB in LPS-stimulatedcells was measured. RAW cells were seeded at 5×10⁵/well in 6-well platesat 37° C. overnight in 10% FBS complete medium. Cells were washed 2×with 0.5% FBS medium and then pretreated with 10 μM of Compound 11,rosiglitazone, or 15dPGJ₂ at 37° C. for 1 hr. After pretreatment, cellswere incubated with 0.5% FBS medium or stimulated with 1 μg/ml LPS at37° C. for 15 min. After being washed 3× with cold PBS, cells were lysedto generate whole cell lysates. The protein concentrations weredetermined and 5 μg protein of whole cell lysate was used to determinethe NF-kB p65 activity for each sample using a commercial ELISA kit(Active Motif, Carlsbad, Calif.). In this ELISA, micro-well plates arecoated with an oligonucleotide containing the consensus binding site forNF-kB. After addition of the cell lysate, DNA-bound transcription factoris detected using anti-p65 antibodies. Two wells of each sample wereassayed and the mean of two ELISA readings for each sample wasdetermined. The specificity of the binding was checked by subsequentaddition of 20 pmol of wild-type consensus oligonucleotide to each well.

As shown in FIG. 15, both Compound 11 and 15dPGJ₂ inhibited theactivation of NF-kB. By contrast, rosiglitazone, a strong agonist ofPPAR-gamma, did not inhibit the production of p65 transcription factor.

FIGS. 13A-D illustrate the suppression of collagen-induced arthritis bytreatment with Compound 11. Arthritis was induced by intradermaladministration of collagen (100 μg/mouse) in complete adjuvant in makeDBA/1 Lac mice of 7 weeks. The booster (100 μg/mouse) immunization inincomplete adjuvant was given subcutaneously on Day-21. Two days laterwhen arthritic scores were around 1, the animals were divided into twogroups. One group received 50 mg/kg dose of Compound 11 orally for 17days daily. The second group received 10% PEG in water and was used as avehicle treated group. Body weight (FIG. 13A), Clinical score (FIG.13B), Joints affected (FIG. 13C) and Paw thickness (FIG. 13D) weremonitored 24 hours after the drug administration at different timeintervals. As shown in the Figures, the mice treated with Compound 11showed significantly lower clinical scores, joints affected and pawthickness when compared to the vehicle treated group. There was nochange in body weight between the vehicle and the treatment groups.

Experimental allergic encephalomyelitis (EAE) is an autoimmunedemyelinating inflammatory disease of the central nervous system. EAEexhibits many of the clinical and pathological manifestations of humanmultiple sclerosis (MS), and it serves as an animal model to testpotential therapeutic agents for MS (Scolding et al, Prog Neurobiol,43:143-73, 2000). FIG. 14 illustrates the suppression of EAE by Compound11. Active EAE was induced in SJL-/J mice essentially according to themethod of Owens and Sriram (Neurol Clin, 13:51-73, 1995). Naive micewere immunized subcutaneously with 400 pg each of mouse spinal cordhomogenate in complete Freund's adjuvant on day 0 and day 7. Mice werethen treated once daily by subcutaneous injection with 50 μg or 200 μgof compound 11 or with vehicle only. Paralysis was graded according tothe numeric scale indicated. As evidenced by the dramatic reduction inclinical score shown in FIG. 14, treatment with the 200 μg dose ofcompound 11 was highly effective in ameliorating EAE. It will be evidentfrom the above that the compounds according to the present invention, asrepresented by compound 11, not only lower blood glucose level,triglyceride level, free fatty acid level, glycohemoglobin and seruminsulin, but also raise the leptin level while showing no significantincrease in body weight or liver toxicity. The compounds also inhibitTNF-alpha, IL-6, IL-1-beta production and COX-2 activity in vitro and,as shown by FIGS. 13A-13D and 14, the compounds can be used to suppressarthritis and potentially to treat multiple sclerosis, respectively. Theproperties demonstrated above indicate that the compounds of theinvention should be useful in the treatment of disorders associated withinsulin resistance, hyperlipidemia, coronary artery disease andperipheral vascular disease and for the treatment of inflammation,inflammatory diseases, immunological diseases and cancer, especiallythose mediated by cytokines and cyclooxygenase.

While the invention has been exemplified above by reference to thepreparation and use of compound 11, it will be understood that theinvention is of broader application consistent with the scope ofcompounds represented by formula 1. This includes, for example, compound10, which is not only useful as an intermediate for preparing compound11 as shown but also demonstrates useful biological activity of its ownconsistent with the activities of compound 11.

The synthesis of other compounds representative of the scope of theinvention is illustrated by the examples which follow.

EXAMPLE 23-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylamide(24)

Compound 24, which may be represented by the formula:

was prepared as follows from compound 14. A clean dry flask with stirbarwas charged with compound 14 (0.423 g, 0.837 mmol) and dry DMF (10 mL).Then with stirring carbonyldiimidazole (0.271 g, 1.67 mmol) was addedand the reaction was heated to 60° C. for 1 h. while vented through anoil-bubbler. The reaction mixture was then cooled to 0° C. and 2Mammonia in methanol (2.1 mL, 4.2 mmol) was added. The reaction wasworked up by partitioning the mixture with 10% citric acid (10 mL),ethyl acetate (50 mL), and water (40 mL). The organic phase was thenrinsed sequentially with water (2×30 mL), brine (1×20 mL) and dried withanhydrous MgSO₄. Concentration of the organics afforded crude product.The crude product was purified by silica gel chromatography using ethylacetate-hexanes (1:1) containing 1% acetic acid to ethyl acetate-hexanes(3:2) containing 1% acetic acid gradient elution. Concentration of theappropriate fractions yielded 200 mg (47%) of the white-light yellowprimary amide as a solid. Analysis: ¹H NMR, 400 MHz (DMSO-d₆): δ12.06(br, 1 H), 7.40 (s, 1 H), 7.34 (br, 1 H), 7.27 (d, J=8.4 Hz, 2H), 7.18(d, J=8.8 Hz, 2H), 7.05 (d, J=9.2 Hz, 2H), 6.98(d, J=8.4 Hz, 2H), 6.93(br, 1 H), 6.36(m, 1 H), 6.20 (s, 1 H), 6.19 (s, 1 H), 4.91(dd, J=4.0Hz, 1 H), 3.57 (s, 6H), 3.12 (dd, J=9.2 Hz, 1 H).

EXAMPLE 33-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5ylmethyl)-phenoxy]-phenyl}-N,N-dimethylacrylamide(25)

Compound 25, represented by the formula:

was prepared as follows: A clean dry flask with stirbar was charged withcompound 14 (0.422 g, 0.835 mmol) and dry DMF (1 mL). Then with stirringcarbonyldiimidazole (0.271 g, 1.67 mmol) was added and the reaction washeated to 60° C. for 1 h. while vented through an oil-bubbler. Thereaction mixture was then cooled to 0° C. and a 2M dimethylamine in THF(2.1 mL, 4.2 mmol) solution was added. The reaction was worked up bypartitioning the mixture with 10% citric acid (10 mL), ethyl acetate (50mL), water (40 mL). The organic phase was then rinsed sequentially withwater (2×30 mL), brine (1×20 mL) and dried with anhydrous MgSO₄.Concentration of the organics afforded crude product. The crude productwas purified by silica gel chromatography using ethyl acetate-hexanes(3:2) containing 1% acetic acid elution. Concentration of the fractionsyielded 381 mg (86%) of the off-white tertiary dimethylamide as a solid.Analysis: ¹H NMR, 400 MHz (DMSO-d₆): δ11.97 (br, 1H), 7.29 (d, J=8.8 Hz,2H), 7.27 (d, J=8 Hz, 2H), 6.99 (d, J=8.8 Hz), 6.95(d, J=8.8 Hz, 2H),6.57 (s, 1 H), 6.35 (m, 1 H), 6.29 (s, 1 H), 6.28 (s, 1 H), 4.91(dd,J=4.4 Hz, 1 H), 3.58 (s, 6H), 3.12 (dd, J=9.2 Hz, 1 H), 3.05 (br, 3H),2.91 (s, 3H).

EXAMPLE 43-(3,5-Dimethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-N-methoxy,-N-methylacrylamide(compound 26)

Compound 26 may be structurally shown as follows:

was prepared as follows. A clean dry flask with stirbar was charged withcompound 14 (0.450 g, 0.890 mmol) and dry DMF (1 mL). Then, withstirring, carbonyldiimidazole (0.29 g, 1.78 mmol) was added and thereaction was heated to 60° C. for 1 h. while vented through anoil-bubbler. The reaction mixture was then cooled to 0° C. andN-methyl-N-methoxyhydroxylamine hydrochloride (0.434 g, 4.45 mmol) inwater (1 mL) and triethylamine (0.62 mL) was added and stirredovernight. The reaction was worked up by partitioning the mixture with10% citric acid (10 mL), ethyl acetate (50 mL), and water (40 mL). Theorganic phase was then rinsed sequentially with water (2×30 mL), brine(1×20 mL) and dried with anhydrous magnesium sulfate. Concentration ofthe organics afforded crude product. The crude product was purified bysilica gel chromatography using ethyl acetate-chloroform (1:5) elution.Concentration of the appropriate fractions yielded 400 mg (82%) of theoff-white tertiary N-methyl-N-methoxyamide as a solid. Analysis: ¹H NMR,400 MHz (DMSO-d6): δ12.06 (br, 1 H), 7.27 (d, J=9.2 Hz, 2H), 7.26 (d,J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz), 6.95 (d, J=8.4 Hz, 2H), 6.57 (s, 1H), 6.35 (m, 1 H), 6.29 (s, 1 H), 6.28 (s, 1 H), 4.91(dd, J=4.4 Hz, 1H), 3.58 (s, 6H), 3.12 (dd, J=9.2 Hz, 1 H), 3.05 (br, 3H), 2.91 (s, 3H).

EXAMPLE 5

The syntheses shown in this example are illustrated in Scheme 6.

2-(4-Acetoxyphenyl)-3-p-tolylacrylic acid (37). To a mixture of(4-hydroxyphenyl)-acetic acid (18.3 g, 120.3 mmol) and4-methylbenzaldehyde (12.0 g, 100 mmol) in 250 mL acetic anhydride wasadded potassium carbonate (11.9 g, 121.2 mmol). The reaction mixture wasstirred at 80° C. for 16 h before it was cooled to room temperature. Tothe mixture was added 100 mL H₂O, 5% HCl in water to pH 1 and 200 mLethyl acetate. The mixture was then heated to 80° C. until all ethylacetate was evaporated. The precipitate was filtered and washed withwater and hexane. The filter cake was recrystallized out of toluene,filtered, washed with hexane and dried under vacuum to yield a paleyellow powder (20.16 g, 68.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s,1H), 7.74 (s, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.01(d, J=8.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H).

2-(4-Hydroxyphenyl)-3-p-tolylacrylic acid (38). To a solution ofcompound 37 (20.16 g, 68.1 mmol) in 100 mL THF was added a solution oflithium hydroxide (5.7 g, 237.5 mmol) in 100 mL water. The reaction wasallowed to stir at room temperature for 16 h after which 5% HCl in waterwas added to pH=1. The yellow solid was filtered and recrystallized outof toluene, washed with hexane and dried under vacuum to yield a whitesolid (14.27 g, 82.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (br s, 1H),9.47 (br s, 1H), 7.63 (s, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 2.22 (s, 3H).

2-[4-(4-Formylphenoxy)-phenyl]-3-p-tolylacrylic acid (39). To a solutionof 38 (7.27 g, 28.6 mmol) and potassium carbonate (8.68 g, 62.9 mmol) in200 mL N,N-dimethylacetamide was added 4-fluorobenzaldehyde (3.9 mL,36.4 mmol). The reaction mixture was heated to 190° C. for 1.5 h underargon then cooled to room temperature. The addition of 5% HCl in waterto pH 1 resulted in the product separating out as oil. Approximately 50mL ethyl acetate was added to the mixture which is allowed to stir 16 h.The solid was collected and recrystallized out of toluene, rinsed withhexane and dried under vacuum to yield a white powder (8.1 g, 79.0%). ¹HNMR (400 MHz, DMSO-d₆) δ 12.71 (s, 1H), 9.94 (s, 1H), 7.97 (d, J=8.8 Hz,2H), 7.76 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 7.16(d, J=6.4 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 2.25(s, 3H).

2-{4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid (40). To a solution of 39 (4.0 g, 11.2 mmol),thiazolidine-2,4-dione (1.31 g, 11.2 mmol), and benzoic acid (1.64 g,13.4 mmol) in 100 mL toluene was added piperidine (1.66 mL, 16.8 mmol).The mixture was vigorously refluxed with Dean Stark apparatus for 1.5 hunder argon then cooled to room temperature. 5% HCl was added to pH 1.The solid was filtered, recrystallized out of toluene, filtered, andwashed with hexane before drying under vacuum to a yellow solid(quantitative). ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (br s, 1H), 12.59 (brs, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.22 (d,J=9.2 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.12 (d, J=9.2 Hz, 2H), 7.07 (d,J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 2.25 (s, 3H).

2-{4-[4-(2,4-Dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid (41). To a solution of 40 (1.0 g, 2.2 mmol) and ammonium formate(8.32 g, 132 mmol) in 25 mL glacial acetic acid was added 5% Pd/C (1.0g). The mixture was refluxed for 7.5 h, cooled to room temperature andfiltered over Celite. The mixture was concentrated in vacuum then addedto 200 mL water. The product was filtered and washed with hexanes. Thesolid was recrystallized out of toluene, cooled to room temperature andsonicated until the solid was observed. The mixture was then stirred atroom temperature for 16 h. The precipitate was collected and washed withhexanes to yield a white solid (0.609 g, 59.1 %). ¹H NMR (400 MHz,DMSO-d₆) δ 12.65 (s, 1H), 12.05 (br s, 1H), 7.72 (s, 1H), 7.30 (d, J=8.8Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 4.92 (dd, J=4.4and 9.6 Hz, 1H), 3.38 (dd, J=4.4 and 14.0 Hz, 1H), 3.21 (dd, J=9.2 and14.0 Hz, 1H), 2.24 (s, H).

2-{4-[4-(2,4-Dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-p-tolylacrylicacid methyl ester (42). To a mixture of 41 (0.1 g, 0.218 mmol) and BOP[Castro's Reagent,Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate] (0.144 g, 0.326 mmol) in 5 mL dichloromethane wasadded triethylamine (0.067 mL, 0.477 mmol). The mixture was stirred for1 h, and then sodium methoxide (0.5 M solution in methanol, 0.07 mL,0.035 mmol) was added with 5 mL MeOH. The reaction was allowed to stirat room temperature for 16 h. 5% HCl was added to pH 0 and the mixturewas extracted with 25 mL dichloromethane three times. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was loaded onto silica gel column as asolution in dichloromethane. The product was eluted with hexanes-ethylacetate (3:2). Fractions were concentrated in vacuum to a white solid(0.037 g, 36.4%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (br s, 1H), 7.75 (s,1H), 7.30 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.0 Hz,2H), 7.02 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.0 Hz,2H), 4.91 (dd, J=4.8 and 9.6 Hz, 1H), 3.72 (s, 3H), 3.39 (dd, J=4.0 and13.6 Hz, 1H), 3.13 (dd, J=9.2 and 14.0 Hz, 1H), 2.25 (s, 3H).

EXAMPLE 6

The syntheses shown in this example are illustrated in Scheme 7.

3,5-dimethylbenzaldehyde (43). To a mixture of 3,5-dimethylbenzoic acid(7.51 g, 50 mmol) and triethylamine (21 mL, 150 mmol) in dichloromethane(200 mL) was added BOP reagent (22.11 g, 50 mmol). The solution wasstirred at room temperature for 20 min and thenN,O-dimethylhydroxylamine hydrochloride (5.0 g, 50 mmol) was added.After an additional 10 min, triethylamine (7 mL, 50 mmol) was added andthe mixture was stirred for another 0.5 h. The solvent was removed invacuo and the mixture was redissolved in ethyl acetate (300 mL), washedwith 1N HCl (200 mL), 1N NaOH (200 mL), water, brine then dried (MgSO₄),filtered and concentrated in vacuo to yield a colorless syrup (6.25 g).This material was dissolved in THF (250 mL) and cooled to 0° C. underargon atmosphere. A solution of DIBAL [diisobutylaluminum hydride] (1Min THF, 50 mL) was added to the stirring solution over 5 min. After 20min of stirring, additional DIBAL (20 mL) was added. After an additional15 min, the reaction was quenched with careful addition of 1N HCl (300mL) and the product was extracted into ethyl acetate (300 mL), washedwith water (2×200 mL), brine (200 mL), dried (MgSO₄), filtered andconcentrated in vacuo to yield 43 (4.97 g, 74% overall).

3-(3,5-Dimethylphenyl)-2-(4-hydroxyphenyl)-acrylic acid (44). To amixture of 43 (3.23 g, 24 mmol), 4-hydroxyphenylacetic acid (3.66 g, 24mmol) and potassium acetate (2.83 g, 28 mmol) was added acetic anhydride(100 mL). The mixture was heated to reflux for 4 h, cooled to roomtemperature, and then poured over water (400 mL). After stirring for 1.5h, a solid gum settled to the bottom and the supernatant was decanted.To the residue was added THF (100 mL) and 1N NaOH (150 mL) and themixture was stirred for 30 min. The mixture was acidified with 1N HCl(200 mL) and the product was extracted into ethyl acetate (300 mL),washed with water (300 mL), brine (300 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The crude solid was crystallized in toluene toyield 2.65 g (42%) of a pale yellow solid 44.

3-(3,5-Dimethylphenyl)-2-[4-(4-formylphenoxy)-phenyl]-acrylic acid (45).To a solution of 44 (2.65 g, 10 mmol) in DMF (20 mL) was added sodiumhydride (60% dispersion in mineral oil, 0.88 g, 22 mmol). After gasevolution ceased 4-fluorobenzaldehyde (1.60 g, 15 mmol) was added andthe reaction was stirred for 16 h. The mixture was poured over 10%citric acid (100 mL), after which a bright yellow solid formed. Thesolid was washed with water and then the wet solid was azeotroped andrecrystallized from toluene to yield 2.97 g (80%) of a yellow solid 45.

3-(3,5-Dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylicacid (46). In a 100 mL round-bottomed flask equipped with a Dean-Starkapparatus, a mixture of 45 (1.55 g, 4.2 mmol), 2,4-thiazolidinedione(0.5 g, 4.2 mmol), benzoic acid (0.62 g, 5.0 mmol) and piperidine (0.62mL, 6.3 mmol) was azeotroped in toluene (60 mL) for 45 min undervigorous reflux. The reaction mixture was cooled then poured over 10%citric acid (40 mL) and stirred until a bright yellow solid formed. Thesolid was filtered and washed with water and the wet solid wasazeotroped and recrystallized from toluene to yield 1.83 g (93%) of 46.¹H NMR (400 MHz, DMSO-d₆): δ 12.72 (br s, 1H), 12.57 (br s, 1H), 7.77(s, 1H), 7.70 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H),7.14 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.69 (s,2H), 2.16 (s, 6H).

3-(3,5-Dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid (47). A mixture of 46 (1.83 g, 3.9 mmol), ammonium formate (4.90 g,78 mmol) and 10% Pd on alumina (2.0 g) was refluxed for 15 h. Thereaction mixture was cooled to room temperature and the catalyst wasfiltered off. Product was separated out with addition of water and thesolid was filtered. The wet solid was azeotroped and recrystallized fromtoluene to yield 0.81 g (44%) 5. ¹H NMR (400 MHz, DMSO-d₆): δ 12.68 (brs, 1H), 12.05 (br s, 1H), 7.68 (s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.16 (d,J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (s,1H), 6.62 (s, 2H), 4.92 (dd, J=8.8 and 4.4 Hz, 1H), 3.37 (dd, J=14.0 and4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.12 (s, 6H).

3-(3,5-Dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid benztriazol-1-yl ester (48). To a mixture of 47 (0.81 g, 1.7 mmol)and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) in dichloromethane (20mL) was added BOP reagent (0.76 g, 1.7 mmol). After 45 min of stirringat room temperature, the mixture was diluted with ethyl acetate (150 mL)then washed with 1N HCl (100 mL), water (100 mL), brine (100 mL), dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using hexanes:ethyl acetate (3:2). Thesolid obtained after concentration was further triturated withhexanes:ethyl acetate (4:1) to yield 0.75 g (76%) of 48.

3-(3,5-Dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester (49). To a solution of 48 (240 mg, 0.4 mmol) inmethanol (10 mL) was added sodium methoxide (0.5 N in methanol, 2 mL).After 10 min the mixture was diluted with 1N HCl (2 mL) and the productwas extracted into ethyl acetate (50 mL), washed with water (50 mL),brine (50 mL), dried (MgSO₄), filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography using hexanes:ethylacetate (3:2) to yield 49 (122 mg, 62%) as a white foam. ¹H NMR (400MHz, DMSO-d₆): δ 12.10 (br s, 1H), 7.71 (s, 1H), 7.28 (d, J=8.8 Hz, 2H),7.18 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H),6.92 (s, 1H), 6.68 (s, 2H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.73 (s,3H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H),2.12 (s, 6H).

5-(4-{4-[2-(3,5-Dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione(50). To a suspension of 48 (116 mg, 0.2 mmol) in dichloromethane (5 mL)at room temperature was added morpholine (87 μL, 1 mmol). Solutionbecame clear. After 10 min the mixture was treated with 10% citric acid(4 mL). The dichloromethane layer was dried (MgSO₄) and directly loadedonto a column which was eluted with hexanes:ethyl acetate (2:3) to yield50 (104 mg, 86%) as a white foam. ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (brs, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.85 (s, 1H), 6.72 (s, 2H), 6.61 (s,1H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.59 (bs, 8H), 3.37 (dd, J=14.0and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.13 (s, 6H).

EXAMPLE 7 Synthesis of5-(4-{4-[2-(4-methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione(54) (see Scheme 8)

5-(4-Hydroxybenzylidene)-thiazolidine-2,4-dione (51). To a mixture of4-hydroxybenzaldehyde (3.67 g, 30 mmol), 2,4-thiazolidinedione (3.51 g,30 mmol) and benzoic acid (4.40 g, 36 mmol) in toluene (100 mL) wasadded piperidine (4.5 mL, 45 mmol) and the mixture was equipped with aDean Stark apparatus and brought to a vigorous reflux. After 45 min themixture was cooled in an ice bath and the supernatant was decanted. Thebright yellow solid was made into a suspension by the addition ofglacial acetic acid (100 mL) and filtered through a Buchner funnel toyield a pale yellow solid (6.00g, 90%). ¹H NMR: (400 MHz, DMSO-d₆): δ12.45 (bs, 1H), 10.30 (s, 1H), 7.70 (s, 1H), 7.45 (d, J=8.8 Hz, 2H),6.91 (d, J=8.8 Hz, 2H).

5-(4-Hydroxybenzyl)-thiazolidine-2,4-dione (52). To a suspension of 51(6.00 g, 27 mmol) in glacial acetic acid (100 mL) was added ammoniumformate (6.27 g, 100 mmol) and 10% Pd on carbon (5.80 g) and the mixturewas heated to vigorous reflux for 16 h. The mixture was cooled to roomtemperature then filtered through Celite. Most of the acetic acid wasremoved in vacuo then the crude product was dissolved in ethyl acetate(250 mL), washed with water (2×250 mL) then brine (250 mL). The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo to yield abeige solid (5.35 g, 85%). ¹H NMR: (400 MHz, DMSO-d₆): δ 11.98 (bs, 1H),9.32 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 4.82 (dd,J=8.4 and 4.0 Hz, 1H), 3.25 (dd, J=14.4 and 4.4 Hz, 1H), 2.99 (dd,J=14.0 and 9.2 Hz, 1H).

4-[4-(2,4-Dioxothiazolidin-5-ylmethyl)-phenoxy]-benzaldehyde (53). To asolution of 52 (5.35 g, 24 mmol) in DMF (150 mL) was added4-fluorobenzaldehyde (3.00 g, 24 mmol) and Cs₂CO₃ (20 g, 62 mmol) andthe mixture was heated to 100° C. for 2 h. The mixture was poured overvigorously string 10% citric acid (200 mL) and ethyl acetate (200 mL).The organic layer was washed with water (300 mL), brine (300 mL), dried(MgSO₄), filtered and concentrated in vacuo. The crude product wastriturated in hexanes-ethyl acetate (2:1) to yield a white solid (5.15g, 65%). ¹H NMR: (400 MHz, DMSO-d₆): δ 12.07 (bs, 1H), 9.92 (s, 1H),7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H),7.09 (d, J=8.4 Hz, 2H) 4.94 (dd, J=8.4 and 4.4 Hz, 1H), 3.41 (dd, J=14.4and 4.4 Hz, 1H), 3.17 (dd, J=14.4 and 9.2 Hz, 1H).

5-(4-{4-[2-(4-Methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione(54). To a suspension of 4-methoxybenzyltriphenylphosphonium-chloride(419 mg, 1.0 mmol) in THF (10 mL) at 0° C. was added solid potassiumtert-butoxide (224 mg, 2.0 mmol). The resultant orange-red solution wasstirred for 15 min at 0° C. then cooled to −45° C. Solid compound 53(327 mg, 1.0 mmol) was added and the reaction mixture stirred for 30 minat this temperature. To this pale yellow solution glacial acetic acid(60 μL, 1 mmol) was added and the solvent was removed in vacuo. Thecrude product was suspended in dichloromethane, adsorbed onto silica geland purified by flash chromatography using hexanes-ethyl acetate (7:3)to yield a white solid (143 mg, 33%) after drying under high vacuum. ¹HNMR: (400 MHz, DMSO-d₆): δ 12.04 (bs, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.24(d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 6.88(d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.53 (d, J=12.4 Hz, 2H), 6.48(d, J=12.0 Hz, 2H), 4.90 (dd, J=9.2 and 4.4 Hz, 1H), 3.36 (dd, J=14.0and 4.4Hz, 1H), 3.11 (dd, J=14.0 and 8.8 Hz, 1H).

EXAMPLE 8

5-(4-{4-[2-(3,5-Dimethoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione(55). To a suspension of 3,5-dimethoxybenzyltriphenylphosphonium bromide(0.82 g, 2.0 mmol) in THF (10 mL) at 0° C. was added solid potassiumtert-butoxide (224 mg, 2.0 mmol). The resultant red solution was stirredfor 15 min at 0° C. then cooled to −₇₈° C. Solid 53 (0.3 mg, 0.90 mmol)was added and the reaction was allowed to warm to room temperature.After 30 min 10% citric acid (50 mL) was added and the mixture waspartitioned between water (50 mL) and ethyl acetate (75 mL). The organiclayer was washed with water (50 mL) and brine (50 mL) then dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using hexanes-ethyl acetate (7:3) toyield 55 as a slightly opaque film (25 mg, 6%) after concentration anddrying under high vacuum. ¹H NMR (400 MHz, DMSO-d₆): δ 12.04 (b s, 1H),7.26 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H),6.91 (d, J=8.4 Hz, 2H), 6.61 (d, J=12.4 Hz, 1H), 6.53 (d, J=12.0 Hz,1H), 6.39 (d, J=2.4 Hz, 1H), 6.36 (t, J=2.4 Hz, 1H), 4.90 (dd, J=9.2 and4.4 Hz, 1H), 3.62 (s, 6H), 3.36 (dd, J=14.0 and 4.4 Hz, 1H), 3.11 (dd,J=14.4, 8.8 Hz, 1H).

EXAMPLE 9

The syntheses shown in this example are illustrated in Scheme 9.

4′-Methoxybiphenyl-3-ol (56). To a solution of 3-hydroxyphenylboronicacid (1.00 g, 7.3 mmol) in 2M aqueous K₂CO₃ (4 mL) was added a solutionof 4-iodoanisole (1.70 g, 7.3 mmol) in acetone (4 mL). A homogeneousmixture was obtained by sequential addition of water (60 mL) and acetone(30 mL). Catalytic Pd(OAc)₂ was added (160 mg, 0.73 mmol) and themixture was stirred for 10 min at room temperature. The acetone wasremoved from the dark brown solution in vacuo and the resultant aqueousmixture was acidified with 1N HCl (20 mL) and extracted with ethylacetate (75 mL). The organic layer was washed with water (50 mL), brine(50 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was suspended in dichloromethane and adsorbed onto silica geland purified by flash chromatography using hexanes-ethyl acetate (3:1)to yield 1.20 g (82%) 56 as a white solid after solvent removal.

4-(4′-Methoxybiphenyl-3-yloxy)-benzaldehyde (57). To a solution of 56(1.20 g, 6.0 mmol) and 4-fluorobenzaldehyde (745 mg, 6.0 mmol) in DMF(25 mL) was added cesium carbonate (3.90 g, 12.0 mmol). After stirringfor 1 h at 100° C., the product was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was washed with water(100 mL), brine (100 mL), dried (MgSO₄), filtered and concentrated invacuo. The crude product was dissolved in dichloromethane and adsorbedonto silica gel and purified by flash chromatography using hexanes-ethylacetate (6:1) to yield 57 (1.23 g, 67%) as a white solid after solventremoval.

5-[4-(4′-Methoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione(58). A mixture of 57 (1.23 g, 4.0 mmol), 2,4-thiazolidinedione (0.48 g,4.0 mmol), benzoic acid (0.60 g, 4.8 mmol) and piperidine (0.61 mL, 6.0mmol) in toluene (30 mL) was heated to a vigorous reflux until most ofthe solvent had evaporated. A yellow suspension was achieved by additionof acetic acid (25 mL) followed by sonication. Filtration of thesuspension followed by washing with acetic acid (10 mL) yielded 58 (1.25g, 75%) after filtration and oven drying. ¹H NMR (400 MHz, DMSO-d₆): δ12.57 (br s, 1H), 7.78 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8Hz, 2H), 7.49 (d, J=5.2 Hz, 2H), 7.36 (t, J=1.6 Hz, 1H), 7.16 (d, J=8.8Hz, 2H), 7.03 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 3.7 (s, 3H).

5-[4-(4′-Methoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione (59).To a suspension of 58 (1.25 g, 3.0 mmol) in acetic acid (30 mL) wasadded ammonium formate (1.50 g, 24 mmol) and 10% Pd on carbon (1.30 g).After vigorous refluxing for 16 h, the mixture was filtered throughCelite, which was subsequently washed with ethyl acetate (100 mL). Themixture was washed with water (2×75 mL), 1N NaHCO₃ (50 mL), brine (75mL) then dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was dissolved in dichloromethane, adsorbed onto silica gel andpurified by flash chromatography using hexanes:ethyl acetate (3:7) toyield a white solid (0.48 g, 38%) after concentration then triturationand filtration from hexanes-ethyl acetate (4:1). ¹H NMR (400 MHz,DMSO-d₆): δ 12.04 (br s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.43 (t, J=7.6 Hz,1H), 7.39 (dt, J=8.0, 1.6 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.22 (t,J=2.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 2H), 4.91 (dd,J=8.8 and 4.4 Hz, 1H), 3.79 (s, 3H), 3.37 ( dd, J=14.4 and 4.4 Hz, 1H),3.13 (dd, J=14.4 and 8.8 Hz, 1H).

EXAMPLE 10

5-[4-(3′,5′-Diethoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione(61). First, 5-[4-(2′,440-dimethoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione (60),was synthesized using a scheme analogous to the synthesis of 58 depictedin Scheme 9. To a suspension of 60 (0.28 g, 0.65 mmol) in acetonitrile(20 mL) was added triethylamine (180 μL, 1.3 mmol), ammonium formate(0.41 g, 6.5 mmol) and 10% Pd on alumina (0.5 g). After refluxing for2.5 h, the mixture was filtered through Celite, which was subsequentlywashed with ethyl acetate (60 mL). The mixture was acidified with 10%citric acid (50 mL) then washed with water (50 mL), brine (50 mL) thendried (MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography using hexanes:ethyl acetate (3:7) toyield a light film (59 mg, 21%) after concentration and drying underhigh vacuum. ¹H NMR (400 MHz, DMSO-d₆): δ 12.04 (br s, 1H), 7.38 (t,J=8.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 2H), 7.22 (d, J=8.4, 1H), 7.20 (dt,J=8.4 and 0.8 Hz, 1H), 7.06 (t, J=2.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H),6.90 (ddd, J=8.0 2.4 and 0.8 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 6.60 (dd,J=8.4 and 2.4 Hz, 1H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.79 (s, 6H),3.37 ( dd, J=14.4 and 4.4 Hz, 1H), 3.13 (dd, J=14.4 and 8.8 Hz, 1H).

EXAMPLE 11

Prevention of Cancellous Bone Loss in Adjuvant Induced Arthritic (AIA)rats

Inflammatory arthritis results in significant peri-articular bone lossdue to activation of cytokines that activate osteoclast activity.Thiazolidinediones (TZD) are insulin sensitizing agents that may inhibitTNF-alpha production, an important factor leading to bone loss ininflammatory arthritis The purpose of this investigation was todemonstrate that the TZD compound 11 and etanercept (p55 TNF solublereceptor) could prevent bone loss in AIA rats. Arthritis was induced inmale Lewis rats (Harlan, weight 150 g) by immunizing them with Freund'sComplete Adjuvant containing Mycobacterium butyricum (100 μg) on thetail base. When the arthritic symptoms began to appear (by day 12-14),the animals were randomized to one of three treatment groups: Group I:vehicle (20% PEG-400 in water, per oral gavage). Group II: compound 11(50 mg/kg, per oral gavage once daily) Group III: etanercept (1.67mg/kg, intra-peritoneal once daily). Each limb was individually scoredfrom 0 (no change or normal) to 4 (marked arthritis with swelling,erythema, nodules, deformation, rigidity) by an observer blinded to thetreatment groups. The body weights, number of limbs affected and hindpaw volume were also noted. On day 11 AIA rats were sacrificed and theright femur and tibia harvested, dissected and fixed in 70% EtOH.Cancellous bone volume and microstructure of the right proximal tibiaand distal femur were accessed by MicroCT (μCT-20, Scanco Medical,Bassersdorf, Switzerland). Results of right proximal tibia are shown inthe following table. TABLE 2 BV/TV Tb.N Conn. Dens C.Th SMI Groups (%)(l/mm) (l/mm3) (μm) (0-3) Sham 21.4 ± 2.6 4.5 ± 0.4 70.5 ± 14.9 250 ± 242.3 ± 0.9 (n = 7) Vehicle  6.2 ± 4.0 2.0 ± 0.4 10.3 ± 15.3 167 ± 27 3.5± 0.3 (n = 12) Comp. 11 13.7 ± 4.7 2.6 ± 0.5 38.3 ± 19.7 186 ± 25 2.8 ±0.3 (n = 9) Etanercept 12.9 ± 5.2 2.8 ± 0.5 31.9 ± 19.7 198 ± 25 2.8 ±0.4 (n = 9)

In summary, significant cancellous bone loss and microarchitecturechanges occurred in AIA rats. However, in this AIA model, nearly 50%less cancellous bone was lost in animals treated with either compound 11or etanercept. Therefore, compound 11 may be effective in reducing boneloss in inflammatory arthritis and similar rapid bone loss states.

EXAMPLE 12

Glucose Uptake

Basal glucose uptake was measured in differentiated 3T3-L1 adipocytesfollowing the protocol of Tafuri (6) with modifications. Briefly, 3T3-L1fibroblasts, obtained from ATCC (Manassas, Va.), were differentiated toadipocytes by treating cells with porcine insulin (1 μg/ml for 4 days),dexamethasone (0.25 μM for first 2 days) and isobutyl methyl xanthine(IBMX, 0.5 mM for first 2 days) (all from Sigma Chemicals, St Louis,Mo.) following the protocol of Frost and Lane (7). Differentiatedadipocytes were incubated in Dulbecco's Modified Eagle Medium (DMEM)containing 10% fetal bovine serum (GibcoBRL, Gaithersburg, Md.) withvarious concentrations of Compound 11 or vehicle (0.1% DMSO) for 48 h in24-well plates, in triplicate. Cells were washed with phosphate bufferedsaline (PBS, 150 mM NaCl, 1 mM KH₂PO₄, 3 mM Na₂HPO₄; pH 7.4) andincubated in glucose-free DMEM for 2 h at 37° C. The cells were washed 3times with Krebs Ringer Phosphate Buffer (KRP). Glucose uptake wasinitiated by addition of 0.25 μCi 2-¹⁴C(U)-deoxy-D-glucose (300μCi/mmol, American Radiolabeled Chemicals Inc., St Louis, Mo.) per welland the cells incubated for 10 min at room temperature in the presenceof 0.1 mmol cold 2-deoxy-D-glucose. Finally, the cells were washed threetimes with ice-cold PBS containing 10 mM cold glucose, lysed with 0.5%SDS, and counted in a scintillation counter (Beckman LS6500).

Transfection and Luciferase Activity Assay

Human PPAR-γ2 expression vector was constructed by inserting PPAR-γ2encoding region into pcDNA3.1+ vector (Invitrogen, Carlsbad, Calif.).Luciferase reporter vector was constructed by ligating PPRE responseelement adjacent to the upstream of Firefly luciferase coding region.Control vector, pRL-SV40 expressing Renilla luciferase was purchasedfrom Promega (Madison, Wis.).

About 2.7×10⁴ 293 cells (ATCC, Manassas, Va.) were plated into a 35 mmculture well and maintained in Eagle's Minimal Essential Medium (ATCC,Manassas, Va.) supplemented with 10% heat inactivated horse serum (ATCC,Manassas, Va.) for 24 hours. Expression, reporter and control vectors(2.5 ng control and 100 ng others per culture well) were transfected byLIPOFECTAMIN PLUS™ Reagent (Invitrogen, Carlsbad, Calif.). Transfectionreagent and DNA were prepared according to manufacture's recommendationsand incubated with cells for 3 hours followed by adding equal volumeEMEM supplemented with 20% horse serum. Twenty-four hours aftertransfection, cells were treated with vehicle or compounds at indicatedfinal concentration for 24 hours. Final concentration of vehicle was0.001% DMSO (Sigma, ST Louis, Mo.) in medium. Vehicle and compoundtreatment were all conducted in triplicate. Each culture well was thenassayed for a response characterized by increased Firefly luciferaseactivity normalized with Renilla luciferase activity.

Assays for Firefly luciferase activity and Renilla luciferase activityfollowed the standard protocol of Dual-luciferase Reporter® Assay System(Promega, Madison, Wis.). Briefly, 400 μl Passive Lysis Buffer was addedinto each culture well and all wells were placed on a shaker for 15minutes. Five μl cell lysate of each well was added to a reaction tube.Luciferase reagent II and Stop & Glo® were injected into the reactiontube sequentially by Sirius Luminometer (Berthold Detection Systems,Pforzheim, Germany). Final reporter activity was calculated as the ratioof Firefly luciferase activity over by Renilla luciferase activity.

Results

The three possible methyl ester analogs with double bond(s) at differentpositions (10, 11, 17), the methyl ester without any double bond 18, thefree acid analog 14 of compound 11, and the Z-isomer 23 of 11 were madeand tested on in vitro glucose uptake in 3T3-L1 cells (Tafuri et al,Endocrinology, 137:4706-12, 1996; Frost and Lane, J Biol Chem260:2646-52, 1985) at 0.1 and 1 μM concentrations (Table 3). At aconcentration of 1 μM compounds 10, 11, and 14 increased glucose uptaketo a level comparable to rosiglitazone. Compounds 17 and 18 showedmodest activity at 1 μM concentration and compound 23 was essentiallyinactive. At a concentration of 0.1 μM, compounds 10 and 11 retainedactivity, but less than that of rosiglitazone. Compound 10, containingtwo double bonds, showed lower increased glucose uptake compared to 11.Compound 17 with only one double bond joined to the TZD ring and thedoubly reduced product 18 were devoid of activity at 0.1 μM. We inferfrom this that the absence of the double bond joined to the TZD ring andthe presence of the cinnamic acid double bond is important for increasedglucose uptake in this system. The lack of activity of 23, thecorresponding Z-isomer of 11, indicates that the geometry of the doublebond is critical to activity. The lower activity of the free acid 14compared to the methyl ester 11 may be due to difference inlipophilicity of the compounds.

Antidiabetic compounds of the TZD class increase peripheral tissuesensitivity to insulin via PPAR-gamma activation. It was our goal tointroduce into diphenylethylene compounds, by chemical modification,this additional mechanism of action. Agonist activity on PPAR-gamma wasexplored in an in vitro system using cells transfected with humanPPAR-gamma2 ligated to firefly luciferase as the reporter element. Theresults from this in vitro transactivation assay for the testedcompounds are summarized in Table 4. The most potent compound in thisseries was found to be 11 (EC₅₀ of 0.28 μM) which had approximatelyone-thirtieth the activity of rosiglitazone (EC₅₀ of 0.009 μM) in thesame assay. Compound 10 (two double bonds) and compound 14 (the freeacid of 11) also showed reasonable potency although less than that ofcompound 11. Compounds 17 and 18, in which the cinnamic acid double bondwas reduced, were essentially inactive.

The Z-isomer 23 showed less than one-tenth the potency of compound 11 inthis assay. Based on these in vitro results, compound 11 was evaluatedin two widely-used mouse models of NIDDM.

Initially, in vivo glucose-lowering efficacy of 11 was explored in thegenetically hyperinsulinemic, diabetic mouse (db/db) model (8 weeks oldmale mice, 5 animals per group) following a single oral dose of 50 mg/kg(in 0.5% CMC and 10% PEG). Blood glucose levels were monitored at timeintervals of 0 min, 1, 4, 6, 24, 48 and 72 h. Compound 11 showed a timedependent glucose lowering effect which was maximal at 24 hrs (23% of 0min, data not shown). Side by side comparison of rosiglitazone andcompound 11 (each at 50 mg/kg/day, orally, for 14 days) showed dramatic,comparable blood glucose lowering effects which increased with durationof dosing (FIG. 16A). Body weights (FIG. 16B) were not affected byeither compound in this short term experiment.

Compound 11 was also evaluated in the genetically obese (ob/ob) malediabetic mouse (7 weeks old male mice, 5 animals per group) withtreatment continued for 14 days at a dose of 50 mg/kg body weight. In 11treated mice blood glucose levels were significantly decreased within 48hours and normalized by three days (*p value<0.05; paired T test) (FIG.17A). Blood glucose levels in these mice rebounded slowly after stoppingtreatment (FIG. 17A). Interestingly, we did not see any increase in bodyweight of drug treated animals compared to vehicle treated group (FIG.17B). This may be an advantageous situation compared to strongPPAR-gamma agonists which showed a large body weight gain in differentanimal models.

After a treatment of fourteen days blood samples were collected fromboth the groups for the determination of glycosylated hemoglobin, seruminsulin, triglycerides, FFA levels (FIG. 18). Glycosylated hemoglobin,which is being used as marker of diabetes management, was reduced from5.2% to 3.8% (p=0.15). 11 reduced serum insulin by 58%, triglycerides by65% and free fatty acid (FFA) levels by 33%, all p<0.05 compared tovehicle treated animals.

To establish the effective dose of 11, a further experiment was carriedout in ob/ob mice (n=8) with three different doses. As shown in FIG. 19there was a dose dependent glucose lowering effect. Animals treated witha dose of 3.12 mg/kg showed a similar extent of glucose reductioncompared to 12.5 mg/kg after twelve days of treatment. Thus, the effectof 11 is comparable with rosiglitazone in both db/db and ob/ob mice.

It has been proposed earlier that the compounds which show high degreeof activation of PPAR-gamma generally have superior glucose loweringactivities in animal experiments (Wilson et al, J Med Chem 39:665-8,1996; Foreman et al, Cell 83:803-12, 1995). However, findings reportedhere differ from this interpretation. We have found a less potentPPAR-gamma agonist 11 which showed a glucose lowering activity inanimals comparable to that of rosiglitazone. Attempts are being made toelucidate further the mechanism behind this potent glucose loweringactivity of 11. Glycogen synthesis in the liver, but particularly in themuscle is major site for the disposal of postprandial glucose. Onepossible explanation for strong glucose lowering activity in spite ofmodest PPAR-gamma agonist activity is our recent observation of higherglycogen synthesis induced by 11 compared to rosiglitazone (see below).TABLE 3 In vitro Glucose Uptake in 3T3-L1 Adipocytes^(a) % Glucoseuptake Compound no. 0.1 μm 1.0 μm  1 (rosiglitazone) 204.2 ± 8.5 214.7 ±36.5 10 142.6 ± 7.4 209.3 ± 22.6 11 161.6 ± 11.4 218.1 ± 10.0 14 108.6 ±19.9 199.5 ± 11.6 17 101.9 ± 6.8 130.0 ± 27.0 18 104.4 ± 5.7 137.0 ±10.1 23  89.5 ± 5.6 118.0 ± 3.6 Insulin 335.2 ± 21.7 345.6 ± 8.3^(a)Basal glucose uptake is expressed as % basal of the non treatedcells (each point is the average of quadruplicate determinations ± SDvalues).

TABLE 4 Induction of PPAR-γ Mediated Luciferase Activity byThiazolidinediones^(a) Compound no. EC₅₀ (μM)  1 (rosiglitazone) 0.009 ±0.007 10 1.136 11 0.284 ± 0.036 (n = 5)^(b) 14 0.690 ± 0.038 (n = 2) 1723.9 18 57.7 23 3.686 ± 1.454 (n = 2)^(a)Results are based on several independent experiments. Eachexperiment contains at least 8 different concentration of drug treatment(between 0.1 to 30 μM), with each concentration in triplicate. EC₅₀values were calculated by non-linear regression analysis using GraphPadPrism software.^(b)n = independent experiments.Conclusion

TZD's based on the alpha-phenyl cinnamic acid motif have glucoselowering activity in genetic models of diabetic mice. Compound 11 showedstrong glucose lowering activity even though it is a weak PPAR-gammaagonist. Strong glucose lowering activity of 11 in spite of being aweaker PPAR-gamma agonist may be due to its higher glycogen synthesiscompared to rosiglitazone. Further investigation is required to fullyelucidate the mechanism(s) of action of this new family of TZDs.

EXAMPLE 13

Glycogen Synthesis

Glycogen synthesis was measured as net conversion of ¹⁴C-D-glucose tocellular glycogen in HepG2 cells as described by Ciaraldi et al,Diabetes 41:975-81, 1992. Briefly, HepG2 cells (ATCC, Manassas, Va.) in6-well plates were treated with Compound 11 or other compounds for 48 h.They were washed with 10 mM HEPES buffer (150 mM NaCl, 5 mM KCl, 1.2 mMMgSO₄, 1.2 mM CaCl₂, 2.5 mM CaCl₂, 10 mM HEPES; pH 7.4) containing 1%BSA. Cells were incubated in the same buffer for 30 min prior toaddition of 0.2 μCi/well of ¹⁴C-D-glucose (5 mM final concentration, 10μCi/mmol, American Radiolabeled Chemicals Inc., St Louis, Mo.). Afterincubation for 2 h at 37° C. the cells were washed with ice-cold PBS andsolubilized with 1 M KOH at 55° C. Converted glycogen was precipitatedby ethanol after addition of 10 mM carrier glycogen. The pellet waswashed and resuspended in water, and an aliquot was counted in ascintillation counter (Beckman LS6500). Total protein was assayed andresults were reported as cpm/mg of protein.

Adipogenesis

Adipogenesis in 3T3-L1 fibroblasts was carried out as described by Wu etal, J Clin Invest 101:22-32, 1998. After two days of growth in 6-wellplates, cells were treated either with vehicle (0.1% DMSO) or withcompounds for ten days. Fresh medium with compounds or vehicle wasreplenished every 48 h. Cells were washed with PBS twice and fixed in10% formalin (Sigma) in PBS. After washing in PBS, cells were stainedwith freshly diluted Oil Red O in isopropanol for 1 h at roomtemperature. The cells were washed five times with PBS and visualizedunder an Olympus BH2 microscope. Quantitative accumulation oftriglyceride was also measured under similar experimental conditions,except in this case cells were plated in 100-mm tissue culture dishes.Triglyceride was extracted with methanol:chloroform (2:1) mixture. Tomonitor the efficiency of recovery, ³H-cholesterol oleate (50,000cpm/well, American Radiolabeled Chemicals Inc., St Louis, Mo.) was addedin each tube as tracer before extraction following the protocol of Brownet al, J Clin Invest 55:783-93, 1975. Extracted triglyceride wasmeasured by a colorimetric assay (GPO-Trinder, Sigma) according tomanufacturer instructions.

Transfection and Transactivation Assays

Human PPARγ2 expression vector was constructed by inserting the PPARγ2cDNA coding region into pcDNA3.1+ vector (Invitrogen, Carlsbad, Calif.).The PPRE-luciferase reporter gene was the kind gift of Dr. KennethFeingold. The control vector, pRL-SV40 containing the Renilla luciferasecDNA was purchased from Promega (Madison, Wis.). About 2.7×10⁴ HEK293human embryonal kidney cells (ATCC) were plated into a 35-mm tissueculture dish and maintained in Eagle Modified Essential Medium (EMEM,ATCC) containing 10% heat-inactivated horse serum for 24 h. Expression,reporter (100 ng/dish) and control (2.5 ng/dish) vectors weretransfected using LIPOFECTAMIN PLUS™ Reagent (GibcoBRL) according tomanufacturer's recommendation. At 24 h after transfection, cells weretreated with vehicle (0.001% DMSO in medium) or compounds at theindicated concentration and incubated for 24 h. Each treatment wasconducted in triplicate. Each culture dish was assayed for fireflyluciferase activity normalized by Renilla luciferase activity to accountfor differences in transfection efficiency. Luciferase activity wasmeasured using the Dual-luciferase Reporter® Assay System (Promega) anda Sirius luminometer (Berthold Detection System, Pforzheim, Germany).

In vivo Studies

All procedures performed were in compliance with the Animal Welfare Actand U.S. Department of Agriculture regulations and were approved by theCalyx Therapeutics Institutional Animal Care and Use Committee. Animalswere housed at 22° C. and 50% relative humidity, with a 12-h light anddark cycle, and received a regular rodent diet (Harlan Teklad, Madison,Wis.) ad libitum with free access to water. Male C57BL/KsJ-db/db andC57BL/6J-ob/ob mice were obtained from Jackson Laboratories (Bar Harbor,Maine) when their age was 5 weeks. Seven-week-old animals were dosedwith Compound 11, rosiglitazone maleate (recrystallized fromcommercially available tablets) or vehicle (0.5% carboxymethyl cellulose(Sigma, St. Louis, Mo.) in water) orally once daily by gavage. Bloodglucose measurements were made with a One Touch Glucose Meter (LifeScan, Inc., Milpitas, Calif.) and/or a glucose oxidase assay (GlucoseTrinder, Sigma, St. Louis, Mo.) prior to administering the next dose andin the fed state. Body weights were monitored throughout the study.Eight-week-old male Zucker diabetic fatty (ZDF-fa/fa) rats (GeneticModels, Indianapolis, Ind.) were kept on 6.5% fat Formulab Diet 5008(PMI Feeds, Richmond, Ind.) for two weeks prior to dosing as describedabove.

Statistical Analysis

Data are presented as the mean±standard error (SE) and statisticalcomparisons were made by t test or ANOVA with Tukey/Kramer post hoctesting where appropriate using StatView 5 software (SAS Institute).

Results

Compound 11 Stimulates Glucose Uptake in vitro

Differentiating 3T3-L1 adipocytes represent an insulin-sensitivecell-culture model for studying glucose uptake and is often used tocharacterize potential antidiabetic compounds. Although TZDs increaseglucose uptake in these cells, both in the absence and presence ofinsulin, the majority of this effect appears to be the result ofnon-insulin-mediated glucose disposal. As shown in FIG. 20A, glucoseuptake was increased to a maximum of 1.33±0.02 (mean±SE) fold over basallevels in response to increasing concentrations of Compound 11(0.01,0.1, 1.0 and 10 μM). We also examined the effect of Compound 11 androsiglitazone on insulin-stimulated glucose uptake in 3T3-L1 adipocytes(FIG. 20B).

There was no difference in dose response curves of glucose uptake inresponse to insulin in the presence (5 μM) or absence of the TZDs.Differences in the maximal responses can be accounted for by theincreased amount of basal glucose uptake in the absence of insulin andeither Compound 11 or rosiglitazone, indicating an additive, notsynergistic, effect on glucose uptake. These results suggest thisenhancement of glucose uptake is mediated through anon-insulin-dependent mechanism, such as an increase in GLUT-1transporters.

In vivo Antihyperglycemic Effect of Compound 11

The antihyperglycemic activity of Compound 11 was examined in severalmodels of type 2 diabetes mellitus. FIG. 21 summarizes the effect ofCompound 11 given as single daily oral doses of 50 mg/kg (96.2 μmol/kg)over 8 to 9 days. At the end of each study the drug led to markeddecreases in blood glucose levels in ob/ob mice (59% vs. baseline),db/db mice (32.% vs. baseline) and ZDF rats (50% vs baseline).

Weight gain in treated and control animals was similar except for ZDFrats, where Compound 11 treated animals gained 13% more weight thancontrol animals. In a subsequent study, the in vivo potency of Compound11 was compared to rosiglitazone in ob/ob mice (FIG. 22). Compound 11and rosiglitazone treatment (both at 10 mg/kg/day; 19.2 and 28.0μmol/kg/day for Compound 11 and rosiglitazone, respectively)demonstrated similar antidiabetic potency over the 8-day treatmentperiod.

Weight gain was similar in vehicle and drug-treated groups. Bothcompounds significantly lower serum insulin, free fatty acids andtriglycerides in this model (data not shown).

Compound 11 is Less Adipogenic than Rosiglitazone

Because TZDs are ligands for PPAR-gamma and induce adipocytedifferentiation (13-15), we sought to determine the adipogenic potentialof Compound 11 using the 3T3-L1 preadipocyte model. In these studies,3T3-L1 fibroblasts were incubated with various concentrations (0.1, 1,10 μM) of Compound 11, rosiglitazone or vehicle in the absence ofdexamethasone, insulin and IBMX. After 14 days cells were stained withOil Red O, counterstained with methylene blue for visual assessment(FIG. 23B) and assayed for triglyceride accumulation. As shown in FIG.23A there was a dose-dependent increase in triglyceride accumulation inresponse to Compound 11 and rosiglitazone. The dose response oftriglyceride accumulation in response to Compound 11 is right-shifted incomparison to rosiglitazone. Moreover, the maximal amount oftriglyceride accumulated in response to Compound 11 was significantlyless than that seen in response to rosiglitazone (3.96 vs. 9.22 foldincrease over control, respectively; P<0.0001, ANOVA). Compound 11 atconcentrations of 100 μM and higher were cytotoxic in this system (datanot shown).

Compound 11 is a Partial Agonist of PPARγ²

We examined the ability of rosiglitazone and Compound 11 totransactivate a PPRE-Luc reporter gene in HEK293 cells cotransfectedwith a human PPAR-gamma2 expression vector. Compound 11 was asubstantially less potent activator of PPAR-gamma than rosiglitazone(FIG. 24). The EC₅₀ for transactivation in this system was 0.009±0.0007μM (SE) for rosiglitazone, and 0.284±0.036 μM for Compound 11 (n=5).Similar dose-response curves were obtained using a reporter-gene assayin cells transfected with heterologous cDNA constructs of GAL4-DNAbinding domain/PPAR-gamma ligand binding domain and 5× upstreamactivator sequence (UAS)-luciferase constructs (data not shown).

Compound 11 Increases Glycogen Synthesis in HepG2 Hepatocytes

The ability of Compound 11 to increase glycogen synthesis was examinedin HepG2 hepatocytes. FIG. 25A shows that there is a dose-dependentincrease in ¹⁴C-glucose incorporated into glycogen in response toCompound 11 in the absence of insulin; this response was maximal(3.1-fold increase over baseline) at 48 to 72 h (FIG. 25B). In contrast,rosiglitazone did not increase glycogen synthesis (0.9-fold decrease at10 μM, FIG. 25A).

In separate experiments, concentrations of rosiglitazone higher than 30μM produced only minimal increases in glycogen synthesis (1.4±0.06, SDfold increase over baseline, data not shown). The increase in glycogensynthesis induced by Compound 11 was dependent upon new proteinsynthesis as it was blocked by cotreatment with cycloheximide (FIG.25C).

Discussion

Our results indicate that Compound 11 is effective in lowering bloodglucose in several animal models of type 2 diabetes. It has a robustantihyperglycemic effect in ZDF rats, where it normalizes glucoselevels. This drug also has potent glucose-lowering activity in ob/obmice, where it appears to be equipotent to rosiglitazone on a massbasis. In actuality Compound 11 appears to be 46% more potent thanrosiglitazone in vivo, on a mole-per-mole basis; the molecular weight ofrosiglitazone is substantially less than Compound 11 (357 vs. 520g/mol), yet the two drugs produced the same degree of glucose-loweringin ob/ob mice. Our results also indicate that Compound 11 issubstantially less adipogenic than rosiglitazone. This effect likelyreflects the lower affinity of Compound 11 for PPAR-gamma in comparisonto rosiglitazone. We did detect a small increase in weight gain in ZDFrats treated with Compound 11, and we were unable to detect differencesin weight gain between rosiglitazone and Compound 11 treated animals inthis short-term study. These data are difficult to interpret because thestudies were conducted in genetically obese animals, which may haveobscured a differential effect of these drugs on weight gain. Severalstudies in normal animals, up to one month in duration, have failed todemonstrate clinically meaningful weight gain (data not shown).

It is widely held that the weight gain associated with TZDs is partlydue to their adipogenic potential, and there has been much effortdirected at finding compounds which are potent PPAR-gamma activators butdo not cause weight gain. Because Compound 11 has less adipogenicactivity, but maintains antihyperglycemic activity, it appears that itmay be possible to develop pharmacologic PPAR-gamma activators thatproduce less weight gain than current commercially available PPAR-gammaactivators. In addition to the contribution of adipogenesis, edema is animportant factor in the weight gain associated with PPAR-gamma agonists.This toxicity is believed to be directly related to the PPAR-gammaactivation potency of the molecule. Because Compound 11 is a weakagonist of PPAR-gamma it may be associated with less edema. Clinicalstudies underway will help define the effect of Compound 11 on bodyweight in humans.

The affinity (Ki) of PPAR-gamma for Compound 11 was 6.5-fold less thanits affinity for rosiglitazone in preliminary competition binding assays(data not shown), and the transactivation potency was as much as 30-foldless than that of rosiglitazone. In general, there is a relativelystrong correlation between PPAR-gamma affinity and glucose-loweringactivity; however, recent data indicate that this relationship may notbe true for all ligands of this receptor. Recently a non-TZD PPAR-gammaactivator, FMOC-L-Leucine, has been shown to have a similar profile toCompound 11. FMOC-L-Leucine has approximately 400-fold less affinity forPPAR-gamma, is only weakly adipogenic, but has potent in vivoantihyperglycemic activity (Rocchi et al, Mol Cell 8:737-47, 2001).Differences in in vivo metabolism may explain part of the apparentdiscrepancy between PPAR-gamma affinity and in vivo antidiabetic potencyfor Compound 11 and other ligands. Studies by Reginato et al (J BiolChem 273:32679-84, 1998), Mukherjee et al (Mol Endocrinol 14:1425-33,2000) and Rocchi et al (Mol Cell 8:737-47, 2001) indicate thatligand-mediated recruitment of the coactivator SRC-1 to PPAR-gamma is animportant determinant for differential activities of ligands. Atpresent, we can only speculate on the way in which Compound 11influences coactivator recruitment to the PPARgamma-RXR complex. It maybe that Compound 11 is less conducive for SRC-1 or PGC-1 recruitmentand, as a result, transcriptional activation. A recent study (Nugent etal, Mol Endocrinol 15:1729-38, 2001) reported that in vitro glucoseuptake into adipocytes is partially independent of PPAR□. Whethernon-PPARgamma-mediated activities or coactivator recruitment explainsthe unique properties of Compound 11 will require further investigation.

Presently, the mechanism by which PPAR-gamma ligands, including TZDs,produce their antihyperglycemic effects is not known. The prevailingwisdom suggests that the glucose-lowering effect of these drugs ismediated through the PPAR-gamma receptor, which enhances insulinsensitivity. Recent data suggest that the relationship betweenPPAR-gamma, its ligands and insulin sensitivity is more complex. Forexample, heterozygous PPAR-gamma null mice actually demonstrateincreased insulin sensitivity, and the insulin sensitizing effect ofsynthetic ligands may result from a balance between transcriptionalactivation and repression (Miles et al, J Clin Invest 105:287-92, 2000).Additionally, a non-receptor mediated mechanism of action for Compound11 and other PPAR-gamma agonists cannot be excluded. Indeed, abrogatingendogenous PPAR-gamma does not result in the elimination of TZD activity(Nugent et al, Mol Endocrinol 15:1729-38, 2001; Chawla et al, Nat Med7:48-52, 2001). Our data indicate that Compound 11, in contrast torosiglitazone, increases glycogen synthesis in liver cells, possiblyproviding an added mechanism for lowering glucose levels in diabeticanimals. Recent data suggest that some non-TZD PPAR-gamma agonists mayupregulate genes involved in glycogen synthesis (Way et al,Endocrinology 142:1269-77, 2001). It is becoming apparent that ligandsfor this receptor will have a spectrum of affinities, transcriptionalactivities, and in vivo pharmacodynamic profiles. Therefore, there issubstantial clinical value in generating compounds with selectivePPAR-gamma modulating activities. The acronym SPRM, for “selective PPARmodulator” (Mukherjee et al, Mol Endocrinol 14:1425-33, 2000), may bestdescribe these molecules. SPRMs may ultimately prove to have bothspecific and tailored activities, including the potential avoidance ofweight gain associated with currently marketed TZDs. Such agents wouldhave the potential to be of great benefit in treating patients with type2 diabetes.

FIG. 20 shows glucose uptake in 3T3-L1 Cells. A. In vitro glucose uptakewas measured in differentiated 3T3-L1 adipocytes after 48-h treatmentwith increasing concentrations of Compound 11 (black bars) or 0.1% DMSOas vehicle (hatched bars). *P≦0.001. B. Glucose uptake in differentiated3T3-L1 adipocytes was measured in the presence of increasingconcentrations of insulin in the presence of vehicle (circles),rosiglitazone (5 μM) (triangles) or Compound 11 (5 μM) (squares).*P≦0.05, #P=0.02 vs. vehicle.

FIG. 21 shows in vivo Antihyperglycemic Activity of Compound 11 inDiabetic Animals. Diabetic ob/ob mice (A) and db/db mice (B) anddiabetic ZDF rats (C) were treated with single daily doses of Compound11 (50 mg/kg=96.2 μmol/kg) (squares) or vehicle (0.5% carboxymethylcellulose) (circles) by oral gavage for 8 or 9 days. Blood glucosemeasurements were made in the fed state. *P≦0.05, #*P≦0.01, †P≦0.001.

FIG. 22 shows in vivo Antihyperglycemic Activity of Compound 11 vs.Rosiglitazone in ob/ob mice. Diabetic ob/ob mice were treated withsingle daily doses of Compound 11 (squares) and rosiglitazone(triangles) at 10 mg/kg (19.2 and 28.0 μmol/kg, respectively) or vehicle(0.5% carboxymethyl cellulose) (circles) by oral gavage. Blood glucose(A) and body weight (B) were measured during the 8-day treatment period.

FIG. 23 shows in vitro Adipogenic Activity of Compound 11. 3T3-L1 cellswere cultured with vehicle, Compound 11 or rosiglitazone for 10 days.Total accumulated triglyceride was measured. (A) Quantitativemeasurement of accumulated triglyceride after 10 days of treatment withincreasing concentrations of Compound 11 (black bars) or rosiglitazone(hatched bars) or vehicle (white bar). (B) Qualitative assessment oftriglyceride accumulation by Oil Red O after 10-day treatment with 1 μMCompound 11, rosiglitazone or vehicle.

FIG. 24 shows induction of PPARgamma-Mediated Transactivation ofPPRE-Luc Reporter by Compound 11 and Rosiglitazone. HEK293 cells weretransiently cotransfected with a PPAR-gamma expression vector and aPPRE-Luc reporter construct. Cells were also transfected with a cDNAconstruct containing Renilla luciferase, which was used to control fortransfection efficiency. Transfected cells were treated with increasingconcentrations of Compound 11 and rosiglitazone. Luciferase activity isexpressed as enhancement over basal levels (no drug) and is correctedfor transfection efficiency. The figure shows a representative result offive experiments.

FIG. 25 shows the effect of Compound 11 on In Vitro Glycogen Synthesisin HepG2 Cells. A. Dose-dependent stimulation of glycogen synthesis fromglucose by Compound 11 in the absence of insulin at 48 h. Stimulation ofglycogen synthesis is expressed as a percentage of basal (vehicle),which is defined as 100%. B. Time-dependent increase in Compound11-stimulated glycogen synthesis. The maximal effect occurs at 48 to 72h of treatment with Compound 11. C. Cycloheximide blocks glycogensynthesis induced by Compound 11 (30 μM, 48 h). Vehicle=white bars,Compound 11=black bars, rosiglitazone=hatched bars, CHX=cycloheximide,checked bars, rosi=rosiglitazone.

Co-Administration

The compounds according to the present invention may be combined with aphysiologically acceptable carrier or vehicle to provide apharmaceutical composition, such as, lyophilized powder in the form oftablet or capsule with various fillers and binders. Similarly, thecompounds may be co-administered with other agents. Co-administrationshall mean the administration of at least two agents to a subject so asto provide the beneficial effects of the combination of both agents. Forexample, the agents may be administered simultaneously or sequentiallyover a period of time. The effective dosage of a compound in thecomposition can be widely varied as selected by those of ordinary skillin the art and may be empirically determined. Moreover, the compounds ofthe present invention can be used alone or in combination with one ormore additional agents depending on the indication and the desiredtherapeutic effect. For example, in the case of diabetes, insulinresistance and associated conditions or complications, including obesityand hyperlipidemia, such additional agent(s) may be selected from thegroup consisting of: insulin or an insulin mimetic, a sulfonylurea (suchas acetohexamide, chlorpropamide, glimepiride, glipizide, glyburide,tolbutamide and the like) or other insulin secretagogue (such asnateglinide, repaglinide and the like), a thiazolidinedione (such aspioglitazone, rosiglitazone and the like) or other peroxisomeproliferator-activated receptor (PPAR)-gamma agonist, a fibrate (such asbezafibrate, clofibrate, fenofibrate, gemfibrozol and the like) or otherPPAR-alpha agonist, a PPAR-delta agonist, a biguanide (such asmetformin), a statin (such as fluvastatin, lovastatin, pravastatin,simvastatin and the like) or other hydroxymethylglutaryl (HMG) CoAreductase inhibitor, an alpha-glucosidase inhibitor (such as acarbose,miglitol, voglibose and the like), a bile acid-binding resin (such ascholestyramine, celestipol and the like), a high density lipoprotein(HDL)-lowering agent such as apolipoprotein A-I (apoA1), niacin and thelike, probucol and nicotinic acid. In the case of inflammation,inflammatory diseases, autoimmune disease and other such cytokinemediated disorders, the additional agent(s) may be selected from thegroup consisting of: a nonsteroidal anti-inflammatory drug (NSAID) (suchas diclofenac, diflunisal, ibuprofen, naproxen and the like), acyclooxygenase-2 inhibitor (such as celecoxib, rofecoxib and the like),a corticosteroid (such as prednisone, methylprednisone and the like) orother immunosuppressive agent (such as methotrexate, leflunomide,cyclophosphamide, azathioprine and the like), a disease-modifyingantirheumatic drug (DMARD) (such as injectable gold, penicillamine,hydroxychloroquine, sulfasalazine and the like), a TNF-alpha inhibitor(such as etanercept, infliximab and the like), other cytokine inhibitor(such as soluble cytokine receptor, anti-cytokine antibody and thelike), other immune modulating agent (such as cyclosporin, tacrolimus,rapamycin and the like) and a narcotic agent (such as hydrocodone,morphine, codeine, tramadol and the like). The combination therapycontemplated by the invention includes, for example, administration ofthe inventive compound and additional agent(s) in a singlepharmaceutical formulation as well as administration of the inventivecompound and additional agent(s) in separate pharmaceuticalformulations.

It will be appreciated that various modifications may be made in theinvention as described above and as defined in the following claims.

1. A compound represented by the following formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R and R′ each independently represent a hydrogenatom; linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl;optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—.
 2. A compound represented by thefollowing formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R independently represents a hydrogen atom;linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;—CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogenatom; optionally substituted linear or branched C₁-C₂₀ alkyl; optionallysubstituted linear or branched C₂-C₂₀ alkenyl; R′ independentlyrepresents a hydrogen atom; linear or branched C₁-C₂₀ alkyl; linear orbranched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″;—CONR₂″″; halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—.
 3. A pharmaceutical compositioncomprising: a therapeutically effective amount of a compound representedby the following formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R and R′ each independently represent a hydrogenatom; linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;halogen atom; optionally substituted linear or branched C₁-C₂₀ alkyl;optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″″each independently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 4. A pharmaceutical composition comprising: a therapeuticallyeffective amount of a compound represented by the following formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R independently represents a hydrogen atom;linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;—CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogenatom; optionally substituted linear or branched C₁-C₂₀ alkyl; optionallysubstituted linear or branched C₂-C₂₀ alkenyl; R′ independentlyrepresents a hydrogen atom; linear or branched C₁-C₂₀ alkyl; linear orbranched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″;—CONR₂″″; halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″represents a cyclicmoiety; Z′ represents a hydrogen atom or a pharmaceutically acceptablecounter-ion; A, A′ and A″ each independently represent a hydrogen atom;C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀ alkoxycarbonyl;C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀ alkylcarboxylamino; carboxyl;cyano; halo; or hydroxy; B, B′ and B″ each independently represent;C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted,linear or branched C₁-C₂₀ alkyl; or optionally substituted, linear orbranched C₂-C₂₀ alkenyl; or A and B jointly, A′ and B′ jointly, or A″and B″ jointly, independently represent a methylenedioxy orethylenedioxy group; and X and X′ independently represent >NH, >NR′″,—O—, or —S—; in a physiologically acceptable carrier.
 5. A method oftreating diabetes comprising: administering to a subject suffering froma diabetic condition, a therapeutically effective amount of a compoundrepresented by the following formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R and R′ each independently represent a hydrogenatom; linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;halogen atom; optionally substituted linear or branched C₁-C₂₀ alkyl;optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 6. A method of treating diabetes comprising: administering to asubject suffering from a diabetic condition, a therapeutically effectiveamount of a compound represented by the following formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R independently represents a hydrogen atom;linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;—CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogenatom; optionally substituted linear or branched C₁-C₂₀ alkyl; optionallysubstituted linear or branched C₂-C₂₀ alkenyl; R′ independentlyrepresents a hydrogen atom; linear or branched C₁-C₂₀ alkyl; linear orbranched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″;—CONR₂″″; halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 7. A method of treating inflammation or inflammatory diseasecomprising: administering to a subject suffering from such condition, atherapeutically effective amount of a compound represented by thefollowing formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R and R′ each independently represent a hydrogenatom; linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;halogen atom; optionally substituted linear or branched C₁-C₂₀ alkyl;optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R ′″; —NH₂;—NHR′″; —NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linearor branched C₁-C₂₀ alkyl; optionally substituted linear or branchedC₂-C₂₀ alkenyl; R′″ independently represents a linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where xrepresents an integer from 1 to 6 and Ar represents aryl; R″″independently represents a hydrogen atom; optionally substituted C₁-C₂₀alkyl; optionally substituted C₁-C₂₀ alkoxy; optionally substitutedC₂-C₂₀ alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ representsa cyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 8. A method of treating inflammation or inflammatory diseasecomprising: administering to a subject suffering from such condition, atherapeutically effective amount of a compound represented by thefollowing formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R independently represents a hydrogen atom;linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;—CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogenatom; optionally substituted linear or branched C₁-C₂₀ alkyl; optionallysubstituted linear or branched C₂-C₂₀ alkenyl; R′ independentlyrepresents a hydrogen atom; linear or branched C₁-C₂₀ alkyl; linear orbranched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″;—CONR₂″″; halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 9. A method of treating immunological disease comprising:administering to a subject suffering from an immunological disease atherapeutically effective amount of a compound represented by thefollowing formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R and R′ each independently represent a hydrogenatom; linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″;halogen atom; optionally substituted linear or branched C₁-C₂₀ alkyl;optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 10. A method of treating immunological disease comprising:administering to a subject suffering from an immunological disease atherapeutically effective amount of a compound represented by thefollowing formula 1:

wherein Z is

n, m, q and r independently represent integers from zero to 4 providedthat n+m≦4 and q+r≦4; p and s independently represent integers from zeroto 5 provided that p+s≦5; a, b and c represent double bonds which may bepresent or absent; when present, the double bonds may be in the E or Zconfiguration and, when absent, the resulting stereocenters may have theR- or S-configuration; R independently represents a hydrogen atom;linear or branched C₁-C₂₀ alkyl; linear or branched C₂-C₂₀ alkenyl;—CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OH; —OR′″; —CONR₂″″; halogenatom; optionally substituted linear or branched C₁-C₂₀alkyl; optionallysubstituted linear or branched C₂-C₂₀ alkenyl; R′ independentlyrepresents a hydrogen atom; linear or branched C₁-C₂₀ alkyl; linear orbranched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″; —NR₂′″; —OR′″;—CONR₂″″; halogen atom; optionally substituted linear or branched C₁-C₂₀alkyl; optionally substituted linear or branched C₂-C₂₀ alkenyl; R″independently represents a hydrogen atom; linear or branched C₁-C₂₀alkyl; linear or branched C₂-C₂₀ alkenyl; —CO₂Z′; —CO₂R′″; —NH₂; —NHR′″;—NR₂′″; —OH; —OR′″; halogen atom; optionally substituted linear orbranched C₁-C₂₀ alkyl; optionally substituted linear or branched C₂-C₂₀alkenyl; R′″ independently represents a linear or branched C₁-C₂₀ alkyl;linear or branched C₂-C₂₀ alkenyl; or —(CH₂)_(x)—Ar, where x representsan integer from 1 to 6 and Ar represents aryl; R″″ independentlyrepresents a hydrogen atom; optionally substituted C₁-C₂₀ alkyl;optionally substituted C₁-C₂₀ alkoxy; optionally substituted C₂-C₂₀alkenyl; optionally substituted C₆-C₁₀ aryl; or NR₂″″ represents acyclic moiety; Z′ represents a hydrogen atom or a pharmaceuticallyacceptable counter-ion; A, A′ and A″ each independently represent ahydrogen atom; C₁-C₂₀ acylamino; C₁-C₂₀ acyloxy; C₁-C₂₀ alkanoyl;C₁-C₂₀alkoxycarbonyl; C₁-C₂₀ alkoxy; C₁-C₂₀ alkylamino; C₁-C₂₀alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy; B, B′ and B″ eachindependently represent; C₂-C₂₀ alkenoyl; aroyl; aralkanoyl; nitro;optionally substituted, linear or branched C₁-C₂₀ alkyl; or optionallysubstituted, linear or branched C₂-C₂₀ alkenyl; or A and B jointly, A′and B′ jointly, or A″ and B″ jointly, independently represent amethylenedioxy or ethylenedioxy group; and X and X′ independentlyrepresent >NH, >NR′″, —O—, or —S—; in a physiologically acceptablecarrier.
 11. A method of inhibiting the activity of TNF-alpha, IL-1,IL-6 or COX-2 which comprises administering to a host in need of suchinhibition an effective amount of a compound according to claim
 1. 12.The method of inhibiting the undesired action of cytokine orcyclooxygenase which comprises administering to a host in need of suchinhibition an effective amount of a compound according to claim
 1. 13.The method of treating a disease mediated by cytokines or cyclooxygenasewhich comprises administering to a host in need of such treatment acompound according to claim
 1. 14. The method of treating insulinresistance which comprises administering to a host in need of suchtreatment an effective amount of a compound according to claim
 1. 15.The method of treating hyperlipidemia which comprises administering to ahost in need of such treatment an effective amount of a compoundaccording to claim
 1. 16. The method of treating coronary heart diseasewhich comprises administering to a host in need of such treatment aneffective amount of a compound according to claim
 1. 17. The method oftreating multiple sclerosis which comprises administering to a host inneed of such treatment an effective amount of a compound according toclaim
 1. 18. The method of treating cancer which comprises administeringto a host in need of such treatment an effective amount of a compoundaccording to claim
 1. 19. A compound according to claim 1 selected fromthe group consisting of:2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid,2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid,2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid methyl ester,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylicacid,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester,5-(4-{4-[2-(3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-(4-{4-[2-(4-methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-(4-{4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-[4-(4′-methoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,5-[4-(4′-methoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,5-[4-(2′,4′-dimethoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,and5-[4-(3′,5′-dimethoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione.20. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound selected from the group consisting of:2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid,2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid,2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylicacid methyl ester,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylicacid,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid,3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylicacid methyl ester,5-(4-{4-[2-(3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-(4-{4-[2-(4-methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-(4-{4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,5-[4-(4′-methoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,5-[4-(4′-methoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,5-[4-(2′,4′-dimethoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,and5-[4-(3′,5′-dimethoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,together with a physiologically acceptable carrier therefor.
 21. Amethod for treating diabetes, comprising: co-administering an effectiveamount of a compound of claim 1 and an agent selected from the groupconsisting of: insulin or an insulin mimetic, a sulfonylurea or otherinsulin secretagogue, a thiazolidinedione, a fibrate or other PPAR-alphaagonist, a PPAR-delta agonist, a biguanide, a statin or otherhydroxymethylglutaryl (HMG) CoA reductase inhibitor, analpha-glucosidase inhibitor, a bile acid-binding resin, apoA1, niacin,probucol, and nicotinic acid.
 22. A method for treating inflammatory orimmunological disease, comprising: co-administering an effective amountof a compound of claim 1 and an agent selected from the group consistingof: a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase-2inhibitor, a corticosteroid or other immunosuppressive agent, adisease-modifying antirheumatic drug (DMARD), a TNF-alpha inhibitor,other cytokine inhibitor, other immune modulating agent, and a narcoticagent.
 23. The compound of claim 1 wherein Z is represented by:


24. The pharmaceutical composition of claim 3 wherein Z is representedby: